Management
of Metabolic
Disease
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
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:
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 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
alloisoleucine

Treatment

These children decompensate within
the first few days of life
– Delayed or missed dx leads to coma and
death

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 +
Acetoacetate
acetyl-CoA +
Propionyl-CoA
Succinyl-CoA
branched-chain -ketoacid dehydrogenase
complex
Propionyl-CoA
Succinyl-CoA
NCA Metabolic Patient
Population

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
Overview
Newborn Screening
 Dietary treatment
 Emergency management
 Long term issues

Newborn Screening
Definition

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
disease
+ gene mutation
+ environmental
exposure
+ 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
reasons
13 states allow exemptions for any reason
– Whether they will use a state-run lab or
contract out to a private lab
 Just
because TMS technology is
used in a state, it does not mean
that that state performs the
“expanded” screen.
Criteria for Newborn Screening
Program

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

http://genes-r-us.uthscsa.edu
Why Does Dietary Treatment
Keep these Kids Alive and Protect
Their Brains?
Because…...

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?
Food
Phenylalanine
Catabolized
tissue
Absent
phenylalanine
hydroxylase
tyrosine
DOPA, NE,
EPI, Melanin
Increased PHE and
Production of
Alternate Products
Phenylalanine
Phenylpyruvate
Phenyllactate
Phenylacetate
tyrosine
Product of Blocked
Reaction
Is Not Made
Phenylalanine
Phenylpyruvate
Phenyllactate
Phenylacetate
tyrosine
DOPA, NE,
EPI,
Melanin
Solution:
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
valine
 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
development
 Maintain normal nutritional status
 Minimize physical manifestations

– MSUD:urine free of branched-chain
ketoacids
– 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
minerals

Extra calories come from “free” foods
Presentation and
Illness are Life
Threatening
Situations!
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
Immediately!

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
Management

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
Formula
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
Feeding
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
MMA
dietary protein
catabolized muscle
Phenylalanine
Restrict
precursor
tyrosine
Supply
Product
8 year old with PKU—Reg
Foods
Breakfast:
Lunch
65
Snack:
Dinner:
14
Snack:
mg Phe Kcal
1 slice white bread
101
67
8 oz medical formula
0
200
1 rice cake w 1 t marg 40
70
1/2 cup noodle soup
103
89
5 saltine crackers
1.4
68
8 oz medical formula
2 c popcorn w 4 t marg
4 oz apple juice
120 g pasta
3 T tomato sauce
0
91
2
745
0.6
200
190
107
445
13
8 oz medical formula
Fruit ice
1/2 oz potato chips
0
10
44
200
124
76
Diet Rx:
Phe: 345 mg
Pro: 52 g
Kcal: 2000
3.5 x PHE Rx
Typical Day’s Intake—LP
Foods
Breakfast:
Lunch
65
Snack:
Dinner:
14
Snack:
mg Phe Kcal
1 slice low pro bread
11
104
8 oz medical formula
0
200
1 rice cake w 1 t marg 40
70
1/2 cup low pro soup 48
67
5 saltine crackers
1.4
68
8 oz medical formula
2 c popcorn w 4 t marg
4 oz apple juice
120 g low protein pasta
3 T tomato sauce
0
91
2
12
0.6
200
190
107
432
13
Diet Rx:
Phe: 345 mg
Pro: 52 g
Kcal: 2000
Reality Check
1 oz cheese 355 mg
8 oz medical formula
Fruit ice
1/2 oz potato chips
0
10
44
200
124
76
1 oz chicken 345 mg
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
Treatment

Compliance
– these diets are complicated!!
– harder to adhere to as the child ages

Cost
– $$$$ medical formula and low protein
foods
– insurance coverage

Repeated blood draws and doctor’s
visits
New Therapies
Liver transplantation in MSUD and MMA
 Gene Therapy

MSUD Symposium 2000
Danvers, MA
Happy
Halloween !!