Inborn Errors of Metabolism

1. Nutrition Support for Inborn
Errors of Protein Metabolism
Dr. Sheetal Mhamunkar
Preventa Clinic
Clinical Dietician & Consultant Sports Nutritionist
Mumbai

2. Protein Disorders
• IEM include inherited biochemical disorders in
which specific enzyme defects interfere with
the normal metabolism of exogenous (dietary)
or endogenous protein
Amino Acid
Organic Aciduria
Urea Cycle Defect

3. Treatment Plan
• Reduce formation, enhance excretion, maintain biochemical
balance of toxic metabolites
• Provide adequate nutrition for proper growth & development
• Supportive care e.g. treatment of infection
• Support for social & emotional development
• Reduction of dietary protein/amino acid remains a mainstay
of treatment. Restriction may require for longer
duration/lifetime in some case
• Typical formula supplementation will be helpful in providing
major portion of protein, energy & other important vitamins
& minerals

4. Amino acid disorders
• Amino Acid Metabolism Disorders are
characterized by the inability to metabolize a
certain essential amino acid.
• The build-up of the amino acid that is not
metabolized can be toxic.
• Treatment of amino acid disorders involves
restricting one or more essential amino acids to
the minimum required for growth and
development
• Supplying the missing product due to the blocked
reaction.

5. Amino Acid Metabolism Disorders
• Phenylketonuria (PKU) (includes clinically
significant hyperphenylalaninemia variants
• Maple Syrup Urine Disorder (MSUD)
• Homocystinuria
• Tyrosinemia

6. Phenylketonuria
• Phenylketonuria (commonly known as PKU) is an
inherited disorder that increases the levels of a
substance called phenylalanine in the blood.
• Phenylalanine is a building block of proteins (an
amino acid) that is obtained through the diet.
• It is found in all proteins and in some artificial
sweeteners.
• If PKU is not treated, phenylalanine can build up
to harmful levels in the body, causing intellectual
disability and other serious health problems.

7. Goals of Nutrition Support: PKU
• Maintain 2-4 hours postprandial plasma PHE & TYR
levels within accepted range
• Support normal growth & development & maintain
appropriate weight
• Maintain normal nutrition status
• Prevent catabolism
• Prevent behavioral abnormalities
• Prevent EEG changes & neurological deterioration in
adults
• Support normal & appropriate wt gain based on ht,
pre-pregnancy weight & gestational age

8. Nutrient Requirement
• Protein: requirements are greater than RDA
when L-amino acids supply measure protein
• Prescribe PHE intake that promotes goals of
nutrition
• Depends on age, growth rate, adequacy of
energy & protein intakes
• Maternal PKU: age, weight gain, trimester of
pregnancy, adequacy of energy & protein
intake & state of health

9. Blood PHE Levels
Age yrs
UK
Germany
France
US
Infant to
10
120 – 360
40 – 240
120 -360
120 – 360
10 -12
< 480
< 600
< 900
120 – 360
12 -20
< 480
< 600
< 900
120 – 600
> 20
< 700
< 1200
< 900
120 – 900
pregnancy
120 - 360

10. RDA for Infants With PKU
Age
PHE
mg/kg
TYR
mg/kg
Protein
g/kg
Calories /kg
Fluid
ml/kg
0 to <
3mo
25 – 70
300 – 350
3.5 – 3.0
120 (145 95)
160 –
135
3 to< 6
mo
20 – 45
300 – 350
3.5 – 3.0
120 (145 95)
160 –
130
6 to < 9
mo
15 – 35
250 – 300
3.0 – 2.5
110 (135 80)
145 -125
9 to <12
mo
10 – 35
250 – 300
3.0 – 2.5
110 (135 –
80)
135 -120

11. RDA For Children With PKU
(boys & girls)
Age yrs
PHE mg/d TYR g/d
Pro g/d
Cals/d
Fluid
ml/d
1 to <4
200-400
1.72 – 3
> 30
1300 (900 900 –
– 1800)
1800
4 to <7
210 -450
2.25 – 3.5
> 35
1700
(1300 –
2300)
1300 –
2300
7 to <11
220 - 500
2.55 - 4
> 40
2400
(1650 –
3300)
1650 –
3300

12. Requirement for Pregnant Women
with PKU
Trimester &
age (yrs)
PHE mg/d TYR g/d
Protein g/d
Energy /d
1st trimester
15 to <19
 19
200 -600
200 -600
5.75 – 7.5
4.5 – 7.0
 75
 70
2,500 (2000 – 3500)
2,500 (2000 – 3500)
2nd trimester
15 to <19
 19
200 -600
200 -600
5.75 – 7.5
4.5 – 7.0
 75
 70
2,500 (2000 – 3500)
2,500 (2000 – 3500)
3rd trimester
15 to <19
 19
200 -600
200 -600
5.75 – 7.5
4.5 – 7.0
 75
 70
2,500 (2000 – 3500)
2,500 (2000 – 3500)

13. Maple Syrup Urine Disease (MSUD)
• MSUD is a group of inherited disorders ILE,
LEU & VAL metabolism resulting from several
mutations
• Some are mild and some are severe
• The condition gets its name from the
distinctive sweet odor of affected infants'
urine

14. Nutrition Support Goals: Acute Illness
or at Diagnosis MSUD
• Don’t wait for conformation of , start
therapy at the earliest.
• Without severe neurologic involvement
Begin high energy feeds; special formulas
as early as possible
• Comatose patients
Begin TPN or nasogastric feeding of BCAA
free & energy within 36 to 48 hrs of
initiation of dialysis

15. Long-term Support MSUD
• ILE, LEU & VAL requirement vary widely from
pt to pt depending on activity branched-chain-ketoacid dehydrogenase (BCKAD)
• Initiate therapy with lowest values
• Changing requirements based on monitoring
• Like PKU protein requirements are higher
• During metabolic acidosis energy needs may
be 25% to 40% higher than normal

16. Nutrient Requirements For Infants &
Children With MSUD
Age
months
ILE mg/kg LEU mg/kg
VAL mg/kg
Pro. g/kg
Cals /d
0 to <3
30 – 60
60 – 100
42 – 70
3.5 to 3
120 (145 – 95)
3 to <6
30 – 50
50 – 85
35 – 60
3.5 to 3
115 (145 – 95)
6 to <9
25 – 40
40 – 70
28 – 50
3 to 2.5
110 (135 - 80)
9 to <12
18 – 33
30 – 55
21 – 38
3 to 2.5
105 (135 – 80)
Boys &
Girls age
Yrs
ILE mg/d
LEU mg/d
VAL mg/d
Protein
g/kg
Cals /d
1 to <4
165 – 325
275 – 535
190 – 400
> 30
1300 (900 – 1800)
4 to <7
215 – 420
360 – 695
250 – 490
> 35
1700 (1300 – 2300)
7 to <11
245 470
410 - 785
285 – 550
> 40
2400 (1650 – 3300)

17. Homocystinuria
• A disorder of methionine metabolism, leading
to an abnormal accumulation of
homocysteine and its metabolites in blood
and urine.
• Homocystinuria is an autosomal recessively
inherited defect in the transsulfuration
pathway (homocystinuria I) or methylation
pathway (homocystinuria II and III)

18. Treatment for Homocystinuria
• Correct primary imbalance in metabolic
relationship
• Supply product of blocked primary pathway
• Protein & energy similar to PKU
• 3g Betaine 2 to 3 times a day with meals help
in significant decline in serum homocystine
concentration

19. • Daily supplement of folate 500 to 1000 g
may be required
• MET 10 to 30 mg/kg for infants; 8 to 12 mg/kg
for children 1 to < 11 yrs; 4 to 14 mg/kg for
women & 6 to 16 mg/kg for men above 11 yrs
• Cystine 200 to 300 mg/kg for infants; 100 to
200 mg/kg for children 1 to < 11 yrs; 25 to 150
mg/kg for women & 25 to 150 mg/kg for men
above 11 yrs

20. Tyrosinemia
• Elevated blood tyrosine levels are associated with
several clinical entities. The term tyrosinemia was
first given to a clinical entity based on
observations that have proven to be common to
various disorders. Types includes
• Transient tyrosinemia of the newborn (TTN)
• Tyrosinemia Ia & 1b
• Tyrosinemia II
• Tyrosinemia III

21. Treatment for Tyrosinemia
• Restrict dietary PHE & TYR to amounts tolerated
for maintaining plasma concentration
• Maintain plasma bicarbonate, phosphate, K+
• Maintain normal liver & kidney function
• In case of elevated serum ammonia, protein
intake may need to be restricted until ammonia
levels return to normal range
• PHE plus TYR 40 to 155 mg/kg for infants; 380 to
1000 mg/d for children 1 to < 11 yrs; 800 to 1200
mg/d for women & 990 to 1500 mg/d for men
above 11 yrs for type 1a & type 1b

22. • PHE & TYR 20 to 90 mg/kg for infants; 250 to
600 mg/d of PHE & 200 to 550 mg/d TYR for
children 1 to < 11 yrs; 270 to 700 mg/d of PHE
& 260 to 500 mg/d of TYR for women & 275 to
750 mg/d of PHE & 260 to 550 mg/d of TYR
for men above 11 yrs for type II & III
• Protein & energy same as PKU for type II &
type III

23. Organic Acid Disorders
• Disorders are characterized by the excretion of
non-amino organic acids in the urine.
• Most of the disorders are caused by a deficient
enzyme involving the catabolism of specific
amino acid(s).
• As a result, the non-metabolized substance
accumulates due to the blockage of the specific
metabolic pathway, which is toxic to certain
organs and may also cause damage to the brain

24. Organic Acid Disorders
•
•
•
•
•
•
•
•
•
Isovaleric Acidemia
3 methylcrotonyl-CoA carboxylase deficiency
Glutaric Acidemia type I
Glutaric Acidemia type II
3 hydroxy-3-methylglutaryl coenzyme A lyase
deficiency
Multiple carboxylase deficiency
Methylmalonic Acidemia
Propionic Acidemia
Beta-ketothiolase deficiency

25. Isovaleric Acidemia
• People with isovaleric acidemia have inadequate levels of
an enzyme that helps break down a particular amino acid
called leucine.
• Health problems range from very mild to life-threatening.
• In severe cases, the features of isovaleric acidemia become
apparent within a few days after birth.
• In these children, episodes of more serious health
problems can be triggered by prolonged periods without
food (fasting), infections, or eating an increased amount of
protein-rich foods.
• LEU 50 to 150 mg/kg for infants; 500 to 900 mg/d for
children 1 to < 11 yrs; 620 to 900 mg/d for women & 1000
to 1500 mg/d for men above 11 yrs
• Protein & energy same as PKU

26. Glutaric Aciduria
• Type I or 2-ketoadipic Aciduria – defect in glutaryl-CoA
dehydrogenase (GDH)
• Initiate nutrition support immediately
• Restrict dietary lysine & tryptophan to amounts of tolerated
to maintain plasma concentrations
• Trial of pharmacologic oral riboflavin if any GDH activity is
present
• Early identification, appropriate medical & nutrition
management in pts treated prior to initial neurologic crises near normal development in most cases

27. • Glutaric Aciduria type II or Multiple Acyl-CoA
Dehydrogenase deficiency characterized by
hypoketotic or nonketotic hypoglycemia & metabolic
acidosis
• Nutrition support with riboflavin, carnitine, & diets
high in CHO, low in protein & low in fat
• In milder or later onset disease has more success
rate than early onset
• Restrict intake of intact protein to  excess essential
isoleucine (ILE), leucine (LEU), lysine
(LYS), tryptophan (TRP) & Valine (VAL)

28. Goals of Nutrition Support
• Maintain 2 to 4 hr postprandial plasma LYS & TRP levels
in low normal range
• Maintain plasma concentration of Glutaric acid
• Support normal growth & development in infants &
children; appropriate wt for ht in adults
• Maintain normal nutrition status: avoid prolonged fasting
• Maintain adequate hydration
• Prevent catabolism & neurological deterioration
• Maintain plasma free carnitine concentration

29. Nutritional Management
• Protein: age; initially high; requirements may be greater
when L-amino acids supply majority of protein due to
rapid absorption; rapid catabolism; possible  total
amino acid absorption
• Energy: sufficient enough for wt gain
• LYS & TRP: age; growth rate; adequacy of energy &
protein
• L-carnitine supplement
• Riboflavin supplement
• Restriction of TRP may require niacin supplement

30. Nutrient requirement
Age
LYS mg/kg
TRP mg/kg
Protein g
Cals/kg/d
0 - <3 months
80-100
10-20
3.5 – 3.0 /kg/d
120 (145 – 95)
3 - < 6 months
70-90
10-15
3.5 – 3.0 /kg/d
115 (145 – 95)
6 < 9 months
60-80
10-12
3.0– 2.5 /kg/d
110 (135 – 80)
9 - < 12
months
50-70
10-12
3.0– 2.5 /kg/d
105 (135 - 80)
1 to <11 yrs
>11 yrs W
> 11 yrs M
35 - 65
10 -40
30 – 45
4 -12
3–6
3–6
> 30g/d
1300 (900-1800)/d

31. Methylmalonic Acidemia (MMA) &
Propionic Acidemia (PA)
• Disorders of essential ILE, MET, THR & VAL & odd
chain fatty acid metabolism
• Severe cases usually present within 1st days of life
• Symptoms in later life are usually milder than
early presenting pts & they may tolerate more
intact protein than pts who present as neonates
• Hypoglycemia & hyperammoninemia may be
present

32. Treatment for MMA & PA
• Oral biotin if PCC activity is present in PA
• Intramuscular hydroxycobalamin if MMA activity is
present in pts with MMA
• Nutrition therapy for vitamin-nonresponsive forms of
PA & MMA is the same
• If blood ammonia is > 35 mol/l or greater than
normal, decrease ILE, MET, THR and/or VAL from intact
protein by 5% to 10% & re-evaluate in 3 days
• Gradually  restricted amino acids as tolerated
• +ve Urine ketoacid suggests catabolism from
insufficient pro & energy intake & impending illness

33. Amino Acid Requirements for MMA &
PA
• Protein energy same as PKU
Age
ILE
MET
THR
VAL
0 to <12 mo
40 – 120
mg/kg
10 - 50
mg/kg
20 – 135
mg/kg
30 - 105
mg/kg
1 to < 11 yrs
485 – 1090
mg/d
180 – 580
mg/d
415 – 885
mg/d
550 – 1225
mg/d
> 11 yrs w
925 – 1470
mg/d
265 – 780
mg/d
790 – 1195
mg/d
790 – 1655
mg/d
> 11 yrs m
540 – 1190
mg/d
290 – 950
mg/d
810 – 1455
mg/d
1080 – 2015
mg/d

34. Urea Cycle Disorders
• Urea Cycle Disorders occur when any defect or
total absence of any of the enzymes or the
cofactors used in the urea cycle results in the
accumulation of ammonia in the blood.
• The urea cycle converts waste nitrogen into urea
and excretes it from the kidneys.
• Since there are no alternate pathways to clear the
ammonia, dysfunction of the urea cycle results in
neurologic damages.
• Hyperammonemia is a biochemical manifestation
of all disorders

35. Treatment
• Restrict dietary protein to amt tolerated without
causing hyperammonemia
• Prevent excessive body protein catabolism
• Restrict dietary TRP to that required for growth to
prevent excess synthesis of serotonin & quinolinic
acid
• Prescribe L-ARG or L-CIT as indicated
• Prescribe sodium benzoate, sodium
phenylacetate or sodium phenylbutyrate to help
decrease accumulated toxic precursors

36. • Amt of protein may need to be increased if these
substances are prescribed daily
• Use essential amino acid mix to supply  50% of prescribed
protein
• Prevent hyperlipdemia
• Energy greater than RDA
• Offer 1.5 ml fluid to neonates & 1 ml fluid to children &
adults for each calorie ingested
• Maintain records of food intake for 3 days before each
blood test
• Evaluate intakes of protein & energy before each blood test

37. Urea Cycle Disorders
• Citrullinemia
• Argininosuccinic aciduria
• Carbamoyl phosphate synthetase deficiency

38. Citrullinemia
• Citrullinemia is urea cycle disorder that
causes ammonia & other toxic substances to
accumulate in the blood
• Type I citrullinemia (also known as classic
citrullinemia. Usually becomes evident in the
first few days of life. Affected infants typically
appear normal at birth, but as ammonia builds
up in the body, they develop symptoms

39. • These medical problems can be life-threatening in
many cases. A milder form of type I citrullinemia is less
common in childhood or adulthood. Some people with
gene mutations that cause type I citrullinemia never
experience signs and symptoms of the disorder.
• Type II citrullinemia usually appear during adulthood
and mainly affect the central nervous system. The
symptoms can be life-threatening, and are known to be
triggered by certain medications, infections,
and alcohol intake in people with this type.

40. Treatment for Citrullinemia
• Immediately restrict dietary protein
• Emphasize other non protein caloric sources to
compensate.
• Intravenous sodium benzoate, sodium
phenylacetate, and arginine are important therapeutic
avenues for reduction of blood ammonia levels.
• In severe cases, hemodialysis may be indicated to
rapidly reduce the blood ammonia level.
• Long-term management requires close dietary
monitoring and oral administration of sodium
phenylbutyrate and arginine.
• In some cases, liver transplant has been successful

41. Tips For Initiation Of Diet
• If  in infancy, initially dietary amino acid requirements are
met by small amounts of breast milk or infant formula
• As feeding skills develop, requirements are met through
small amounts of rice cereal and puréed fruits and
vegetables.
• During the toddler and early childhood years, the amino acid
prescription can be met with low protein cereals, fruits &
vegetables.
• Increased needs of protein are difficult to meet through diet
alone, hence may require larger amount of formula
preparations

42. Expected Outcomes of Good
Treatment
• Blood parameters of toxic metabolites remain
within accepted range
• Adequate growth in height & weight
• Normal intellectual development
• Self management of food choice