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Metabolic disease_Camp


  • pg 1
of Metabolic

Kathryn Camp, MS, RD, CSP
Metabolic disease is all about
    Food and Nutrition
           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 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
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)
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
    Maple Syrup Urine Disease
 Autosomal recessive inheritance
 Infants are normal at birth
 In severe forms, seizures, apnea, and
  death can occur within 10 days of birth
 Branched-chain -ketoacid dehydrogenase
  complex (BCKAD) deficiency
 Elevated levels of branched-chain
  ketoacids, their amino acid precursors, and
   These children decompensate within
    the first few days of life
    – Delayed or missed dx leads to coma and
   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
         Treatment cont:
   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
                  Dietary Protein
             Catabolized Tissue Protein

Leucine            Isoleucine              Valine

-ketoisocaproic -keto-3-methylvaleric -ketoisoval

acetyl-CoA +       acetyl-CoA +            Propionyl-CoA
Acetoacetate       Propionyl-CoA

                    Succinyl-CoA           Succinyl-CoA

 branched-chain -ketoacid dehydrogenase
      NCA Metabolic Patient
   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.
   Methylmalonic acidemia
    – 5 yr old was a frequent flyer; now in
      better control
   Tyrosinemia type 2
    – 1 college student
   PKU
    – 10 mo old
    – A set of 2 yr old identical
      twins, former 25 wk premmies
    – 2 high school students
   Homocystinemia
    – 1 high school student
   MCAD
    – 12 mo old dx on NBS

            Our population changes
            constantly and you never know
            what you might get!
– Good possibility that one or more of
  these kids will be admitted to the ER
  or the Ward on YOUR watch
 Newborn Screening
 Dietary treatment
 Emergency management
 Long term issues
         Newborn Screening
   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.
Child with PKU –
born before NBS
Full expression of
this genetic
+ gene mutation
+ environmental
                          + genetics
                          - exposure
             + genetics
- genetics   + exposure
        Brief History of NBS
   Began in 1963 in MA with screening for PKU
    – Guthrie developed a bacterial inhibition assay for
      phenylalanine using a dried blood filter paper card.
   By 1967, mandatory PKU testing in most states
   70’s and 80’s, 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)
   1990’s, 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)
    Newborn Screening is State
      Public Health Activity
 Federal govt recommends screening for
  PKU, congenital hypothyroidism, and
  sickle cell disease
 Each state is responsible for designing
  and implementing its own program
    – Which disorders to include in the screen
    – Whether parental consent is required
         33 states allow exemptions for religious
          13 states allow exemptions for any reason
    – Whether they will use a state-run lab or
      contract out to a private lab
 Justbecause TMS technology is
 used in a state, it does not mean
 that that state performs the
 ―expanded‖ screen.
Criteria for Newborn Screening
   The Disorder
    – Clearly defined (known)
    – Treatable, with trt initiated in the neonatal period
    – Reasonable incidence
   The Screening Test
    – Rapid turnaround time
    – High sensitivity and specificity
    – Reasonable cost
   Follow-up
    – Locate babies with + screens
    – Provide appropriate referral to CONFIRM diagnosis
      and provide treatment
      Relevance to YOU
 Don’t assume that a reportedly
  ―normal‖ NBS on a sick baby rules out
  the possibility of a metabolic disease
 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
  Why Does Dietary Treatment
Keep these Kids Alive and Protect
         Their Brains?
    Biochemical defect is known
     – absent or minimal production of enzyme system
       that breaks down dietary constituents
    With the amino acidopathies (MSUD, MMA,
     PKU), defect involves dietary constituents
     that are ―essential‖
     – Restrict the precursors to the toxic metabolites
    We can use consequences of the defect to
     design our therapy
    What Happens
    in PKU?                    Absent
Food                         hydroxylase

       Phenylalanine   tyrosine
                       DOPA, NE, EP
                       I, Melanin
 Increased PHE and
    Production of
 Alternate Products
Phenylalanine                   tyrosine


Phenyllactate   Phenylacetate
                      Product of Blocked
                         Is Not Made
Phenylalanine                    tyrosine

     Phenylpyruvate             DOPA, NE,
                                EPI, Melani
Phenyllactate   Phenylacetate
Phenylalanine       tyrosine

                Supply Product
 Four Therapeutic
Strategies to Treat
Amino Acidopathies
1. Enhance Anabolism and
   Depress Catabolism
   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
   Prevent fasting
2. Restrict Toxic Substrate
 MSUD:     leucine, isoleucine, and
 MMA: isoleucine, methionine,
  threonine, valine, odd-chained FA,
  gut origin short-chained fats
   Note: the amino acids are essential and
    sufficient amounts must be provided to
    support normal growth
3. Supplement Conditionally
    Essential Nutrients
  MSUD,     MMA, GA, MCAD
   – Carnitine
        helps excrete organic acids in the urine
  PKU
   – Tyrosine
  Homocystinemia
   – cystine
4. Replace Deficient Cofactors
     MSUD: Thiamin
      – pharmacologic doses
      – 100 to 500 mg oral/day
      – USRDA is 1 mg/day
     MMA: Vitamin B12
      – 1 mg po or IM
     GA: Riboflavin
      – 200 mg/d
Goals of Dietary Treatment
 Correct biochemical abnormalities
 Support normal growth and
 Maintain normal nutritional status
 Minimize physical manifestations
    – MSUD:urine free of branched-chain
    – MMA: urine free of abn organic acids
Designing a Diet for a Person
 with MSUD, PKU, MMA, GA
 Titrated amount of essential amino
  acids are provided by ―whole‖ protein
 Remaining protein needed for body
  growth and maintenance is supplied by
  ―medical formula‖
    – purified amino acid based products
    – also contain CHO, fat, vitamins, and
   Extra calories come from ―free‖ foods
Presentation and
 Illness are Life
               Acute Mgt
   ABC’s
   Hydrate—promote renal excretion of
    offending metabolites
   Treat biochemical derangements
    – Bicarb for acidosis—IV drip
    – IV Glucose (D12 peripherally, more if central)
    – Carnitine—MMA 100-150 mg/kg; MSUD 50 mg/kg
   Withhold whole protein (max 24-48 hrs) to
    prevent further buildup of toxic metabolites
          Acute Mgt, cont
   Remove toxic metabolites
    – Hydration
    – Dialysis (only at presentation in a comatose
      patient with MMA)
   Prevent catabolism
    – Dextrose (>10%)
    – Insulin if needed
   Prevent constipation and promote gut motility
    for MMA
   Prevent increased ICP in MSUD—use zofran
    for nausea
    Initiate Nutrition Support
   High energy feeds
    – 120-150 kcal/kg infants
    – 80-100 kcal/kg children
   If the gut works, use it
   PO, n/g, g-tube
    – metabolic formula without added whole protein
      (initially restrict offending amino acids)
   Notify endocrine service
           Acute Mgt, cont:
 If gut cannot be used or if sufficient
  formula cannot be delivered enterally:
 IV via central line    peripheral line
        hypertonic dextrose        12% dex
        lipids                     lipids
    – replace electrolytes incl 4-6 mEq sodium
   Can use a combination, e.g:
    – drip feeds of formula to supply non-offending
      amino acids + IV dex
Monitoring During Acute Mgt
      MSUD and MMA
   Serum amino acids daily
    – whole blood (green top) to Children’s (M-F)
    – Pediatrix filter paper card (available in endo clinic
      conference room file cabinet) if 3-4 day
      turnaround OK
   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.
   MMA
    – Add VAL as whole protein when levels reach upper
      limits of normal.
Long-Term Dietary
   Using published guidelines, clinical
    picture, and biochemical parameters,
    establish the dietary prescription
    Establish the Dietary Rx
Newly dx 1 month old with MSUD
          Per kg
  LEU:     60-100 mg
  ILE:     36-60 mg
  VAL:     42-70 mg
  Protein: 3-3.5 g
  Kcal: 120
  Fluid: 125-150 ml
 Components of the Medical
 Four ingredients:
  1. Infant formula provides LEU, ILE, VAL
  2. Ketonex-1 provides remaining protein
  3. Polycose provides any needed calories
  4. Water
 Additional ILE and VAL
    – solution of 10 mg purified amino acids/ml
      prepared by pharmacy or parents (if they
      have an appropriate scale)
Metabolic Formulas
Life After Exclusive Formula
 Solid foods are added to the infant’s
  diet in an age appropriate manner
 Begin with cereals and advance to
  vegetables then fruit
 Amounts are calculated using exchange
  lists and food composition tables
 Every bite of food must be weighed!
 Infant/child/adult continues to drink
  medical formula
Foods in the Diet of a Person
   with PKU, MSUD, MMA
NO          meat, poultry, fish,
            dairy, legumes
Limited   grains, vegetables, fruit
Unlimited        pure carbohydrates
                 or fat
            Limited in
dietary protein
catabolized muscle

Phenylalanine        tyrosine

     Restrict        Supply
     precursor       Product
               8 year old with PKU—Reg
                                      mg Phe Kcal
                                                     Diet Rx:
Breakfast:     1 slice white bread    101    67
               8 oz medical formula   0      200     Phe: 345 mg
Lunch          1 rice cake w 1 t marg 40     70      Pro: 52 g
               1/2 cup noodle soup    103    89
                                                     Kcal: 2000
               5 saltine crackers     1.4    68
               8 oz medical formula     0     200
Snack:         2 c popcorn w 4 t marg   91    190
               4 oz apple juice         2     107
Dinner:        120 g pasta              745   445   3.5 x PHE Rx
               3 T tomato sauce         0.6   13
               8 oz medical formula     0     200
               Fruit ice                10    124
Snack:         1/2 oz potato chips      44    76
               Typical Day’s Intake—LP
                                      mg Phe Kcal
                                                        Diet Rx:
Breakfast:     1 slice low pro bread  11     104
               8 oz medical formula   0      200        Phe: 345 mg
Lunch          1 rice cake w 1 t marg 40     70         Pro: 52 g
               1/2 cup low pro soup 48       67
                                                        Kcal: 2000
               5 saltine crackers     1.4    68
               8 oz medical formula      0     200
Snack:         2 c popcorn w 4 t marg    91    190
               4 oz apple juice          2     107
Dinner:        120 g low protein pasta   12    432   Reality Check
               3 T tomato sauce          0.6   13
          14                                         1 oz cheese 355 mg
               8 oz medical formula      0     200   1 oz chicken 345 mg
               Fruit ice                 10    124
Snack:         1/2 oz potato chips       44    76
Cost Comparison of LP Products
and Their Regular Counterparts
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
Shipping and handling runs $5.00 to $25.00 per order
Practical Issues of Dietary
   Compliance
    – these diets are complicated!!
    – harder to adhere to as the child ages
   Cost
    – $$$$ medical formula and low protein
    – insurance coverage
   Repeated blood draws and doctor’s
       New Therapies
 Liver transplantation in MSUD and MMA
 Gene Therapy
MSUD Symposium 2000
    Danvers, MA
Halloween !!

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