Nutrition Support for Inborn Errors of Protein Metabolism

Dr. Sheetal MhamunkarPreventa Clinic

Clinical Dietician & Consultant Sports NutritionistMumbai

Protein Disorders

• IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein

Amino AcidOrganic AciduriaUrea Cycle Defect

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

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.

Amino Acid Metabolism Disorders

• Phenylketonuria (PKU) (includes clinically significant hyperphenylalaninemia variants

• Maple Syrup Urine Disorder (MSUD)• Homocystinuria • Tyrosinemia

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.

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

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

Blood PHE LevelsAge 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

RDA for Infants With PKUAge PHE

mg/kgTYR

mg/kgProtein

g/kgCalories /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

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 – 1800)

900 – 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

Requirement for Pregnant Women with PKU

Trimester & age (yrs)

PHE mg/d TYR g/d Protein g/d Energy /d

1st trimester15 to <19 19

200 -600200 -600

5.75 – 7.54.5 – 7.0

75 70

2,500 (2000 – 3500)2,500 (2000 – 3500)

2nd trimester15 to <19 19

200 -600200 -600

5.75 – 7.54.5 – 7.0

75 70

2,500 (2000 – 3500)2,500 (2000 – 3500)

3rd trimester15 to <19 19

200 -600200 -600

5.75 – 7.54.5 – 7.0

75 70

2,500 (2000 – 3500) 2,500 (2000 – 3500)

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

Nutrition Support Goals: Acute Illness or at Diagnosis MSUD

• Don’t wait for conformation of , start therapy at the earliest.

• Without severe neurologic involvementBegin 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

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

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)

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)

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

• 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

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

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

• 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

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

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

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

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

• 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)

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

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

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 -4030 – 45

4 -123 – 6 3 – 6

> 30g/d 1300 (900-1800)/d

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

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

Amino Acid Requirements for MMA & PA

• Protein energy same as PKUAge 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

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

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

• 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

Urea Cycle Disorders

• Citrullinemia• Argininosuccinic aciduria• Carbamoyl phosphate synthetase deficiency

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

• 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.

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

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

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