Title: Method of preventing development of severe
metabolic derangement in inborn errors of metabolism
United States Patent: 6,503,530
Issued: January 7, 2003
Inventors: Kang; Chunghee Kimberly (16 Forest Gate Cir., Oak
Brook, IL 60523); Kang; David S. (16 Forest Gate Cir., Oak Brook, IL 60523)
Appl. No.: 000204
Filed: November 1, 2001
The present invention provides a method of avoiding rapid development of
extreme hyperammonemia and metabolic acidosis in undiagnosed metabolically
abnormal infants having an inherited metabolic disorder.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention is drawn to a method of providing nutritional
support to a patient with an inborn error of metabolism prior to detection
of the inborn error and prior to development of symptoms. Neonatal-onset of
inborn metabolic disorders often manifest extremely severe hyperammonemia
and/or ketoacidosis leading to permanent neurologic damage unless a prompt
and aggressive treatment is pursued. The present inventors have found that
the severity and onset of metabolic disorders can be substantially reduced
and extended, respectively after birth if the protein content of infant
formulas is controlled for undiagnosed, metabolically abnormal infants
during their early life.
The sudden development of extreme hyperammonemia over about 800 micromoles/dL
of plasma ammonia and severe metabolic acidosis as low as blood pH below 7.0
can be avoided by reducing protein intake to a minimum level required for
normal growth at least during the first two weeks of life until metabolic
screening is completed.
The present invention is used to provide nutritional support that will
suffice the minimum protein requirement for normal growth in human patients
from birth until the time that the testing results for an inborn error of
metabolism are received After birth, all full-term infants receive
conventionally available formulas that contain 1.42 to 1.6 g protein per 100
ml (2.1 to 2.7 g protein per 100 kcal). If protein content is reduced to the
minimum level required for normal growth, the magnitude of clinical and
metabolic severity will be substantially reduced compared with the
full-blown metabolic deterioration. Clinical geneticists often notice less
severe clinical manifestations of metabolic disorders in breast-fed infants
compared with formula-fed infants. For instance, symptoms of classic maple
syrup urine disease (MSUD) normally develop between 4 to 7 days after birth,
whereas breast-feeding sometimes delays onset to the second week of life.
Highly restricted quantities of branched amino acids are usually required
for maintaining normal plasma amino acid level in classic MSUD.
Nevertheless, even the range of 30 percent reduction of protein intake seems
effective to delay the onset of clinical symptoms. Hence, the reduction of
protein within the range allowing normal growth of normal full-term infants
can be used to lessen the severity of metabolic derangement before
establishing diagnosis. Although the protein content of 1.06 g protein per
100 ml (or 1.58 g protein per 100 kcal) in mature human milk is
substantially lower than conventional commercial formulas, postpartum human
milk contains 2.29 g protein per 100 ml (or 3.39 g protein per 100 kcal)
during the first 5 days and 159 g protein per 100 ml (or 2.35 g. protein per
100 kcal) during 6-10 days after delivery. See Table 41-1, The Feeding of
Infants and Children, Nelson Textbook of Pediatrics, 16th ed.
(2000), pp. 155. New mothers, however, typically do not lactate well and the
volume of intake by the breast-fed infant is much lower than the formula-fed
infant. Thus, the delayed onset of clinical symptoms in breast-fed infants
is suspected to be due to a reduced protein intake despite the high protein
content of postpartum human milk. With breast feeding, it is difficult to
adjust the amount of intake. Moreover, the amount of protein intake of
either postpartum or mature human milk is highly variable in each
individual. Hence, breast-feeding lacks the advantage attained by feeding
the infant a calculated amount of a formula having reduced protein with
normal calories and other nutrients. The estimated intake of male breast-fed
infants during the first month is 2.09 g protein per kg of body weight per
day. An infant weighing 3.4 kg consumes usually 630 ml of milk or formula,
which suggests that 1.12 g protein per 100 ml (or 1.66 g protein per 100
kcal) of formula or milk meets this requirement.
The present invention is intended to be used to provide nutritional support
for the general population of full-term newborn infants, including both
normal infants and undiagnosed, metabolically abnormal infants having an
inherited metabolic disorder. Once testing results are received, the normal
infants can be given breast milk or commercially available infant formula.
Since 1.1 g of protein per 100 ml of formula having 20 kcal/oz have provided
normal growth and serum indicators of protein nutritional status, such
formula with 1.3-1.6 g protein per 100 ml (1.9 to 2.7 g protein per 100
kcal) can be continued even after the metabolic evaluation in normal
infants. This suggests a daily intake of 2.4 to 3.0 g protein per kg of body
weight, which exceeds the protein requirement estimated by the factorial
approach (Raiha et al. Protein Nutrition During infancy, Ped Clin North Amer,
1995; 42: 745). However, the present invention is intended to be used to
reduce the severity of metabolic disorder and not as a method of treating
inborn metabolic disorders. Infants diagnosed with metabolic disorders can
be given conventional formula designed for the specific disorder with which
they are diagnosed. However, some metabolic disorders treated by reduced
protein intake can be continued on the composition described herein.
More specifically, the present invention is used to treat infants from day
zero to the day the final report of diagnostic studies for inborn error of
metabolism is received; preferably from day zero to day fourteen; more
preferably from day zero to day ten; and more preferably, from day zero to
Diseases Caused By Inborn Errors of Metabolism
Examples of various disease conditions resulting from inborn errors of
metabolism that can be treated with the method of the present invention
include Maple Syrup Urine Disease, Urea Cycle Disorders, and Organic Acid
Maple Syrup Urine Disease
Maple Syrup Urine Disease (MSUD) or branched chain ketoaciduria is an
autosomal recessive metabolic disorder of panethnic distribution. The
neonatal screening for MSUD is performed either by the Guthrie bacterial
inhibition assay or by tandem mass spectrometry (MS/MS). The worldwide
incidence of MSUD is estimated to be approximately 1:185,000. MSUD is caused
by a deficiency in activity of the branched chain .alpha.-keto acid
dehydrogenase (BCKAD) complex. This metabolic block results in the
accumulation of the branched chain amino acids (BCAA), such as leucine,
isoleucine and valine and the corresponding branched chain .alpha.-keto
acids (BCKA). These infants appear normal at birth, but after a few days
they develop a poor appetite, become apathetic and lethargic, and then
manifest neurologic signs, such as loss of normal reflexes. Alternating
periods of atonia and hypertonicity appear, followed by convulsions and
respiratory irregularities. MSUD is most often accompanied by a
characteristic odor in the urine, perspiration and earwax. If left
untreated, the disease is almost always fatal in the first weeks of life.
Severe MSUD is characterized by plasma BCAA concentrations of:
about .gtoreq.500 micromoles/dL leucine
about .gtoreq.100 micromole/dL isoleucine and
about .gtoreq.100 micromole/dL valine;
and plasma BCKA concentrations of:
about 60 to 460 micromoles/dL .alpha.-ketoisocaproic acid,
about 20 to 150 micromole/dL .alpha.-keto-.beta.-methylvaleric acid, and
about 2 to 35 micromole/dL .alpha.-ketoisovaleric acid
Preventing severe MSUD in a patient means that these levels are not reached
in a patient treated with the method of the present invention and later
diagnosed with MSUD.
Moderate MSUD is characterized by moderately elevated BCAA; for instance,
about 60 to 100 micromoles/dL instead of .gtoreq.100 micromoles/dL leucine.
In classic MSUD at two weeks after birth, the patient is placed on an amino
acid diet from which the branched chain amino acids are omitted, and
supplements of carbohydrates, lipids, vitamins and minerals are added. When
the plasma levels of BCAA are reduced to normal range these amino acids are
added to the diet in highly restricted manner to maintain the plasma levels
within normal or slightly above normal limits.
Urea Cycle Disorders
The urea cycle consists of a series of five biochemical reaction and serves
two purposes: (1) it incorporates nitrogen atoms not retained for net
biosynthetic purposes into which serves as a waste nitrogen product, in
order to prevent the accumulation of toxic nitrogenous compounds; and (2) it
contains several of the biochemical reactions required for the de novo
biosynthesis and degradation of arginine. Interruptions in the metabolic
pathway for urea synthesis are caused by the deficiency or inactivity of any
one of several enzymes involved in specific steps in the cascade. A defect
in the ureageneic pathway has two consequences: arginine becomes an
essential amino acid (except in arginase deficiency, where the enzyme defect
results in a failure of degradation of arginine) and nitrogen atoms
accumulate in a variety of molecules the pattern of which varies according
to the specific enzymatic defect although plasma levels of ammonium and
glutamine are increased in all urea cycle disorders not under metabolic
control. Urea cycle disorders include: (a) carbamyl phosphate synthetase
deficiency (CPSD), (b) N-acetyl glutamate synthetase deficiency, (c)
ornithine transcarbamylase deficiency (OTCD), (d) argininosuccinic acid
synthetase deficiency (ASD), (e) argininosuccinate lyase deficiency (ALD),
and (f) arginase deficiency.
Except ornithine transcarbamylase deficiency, which is an X-linked generic
disorder, urea cycle disorders are inherited by autosomal recessive fashion.
Newborn screening using MS/MS technology can detect argininosuccinate
synthetase deficiency (citrullinemia), argininosuccinate lyase deficiency (argininosuccinicaciduria),
arginase deficiency and hyperammonemia-hyperornithinemia-homocitrullinemia
syndrome (HHH). Once hyperammonemia is identified, other types of urea cycle
disorders can also be diagnosed by biochemical and molecular methods. Great
variability within and among these disorders is due to the difference of
Each of these diseases represents a defect in the biosynthesis of one of the
normally expressed enzymes of the urea cycle and is characterized by signs
and symptoms induced by the accumulation of precursors of urea, principally
ammonium and glutamine. The common pathologic sequlae of these clinical
disorders is the extreme elevation of the plasma ammonia level.
Severe urea cycle disorders are characterized by plasma ammonia level of
about 2,000 to about 2,500 micrograms/dL ammonia and the patient requires a
medical emergency for artificial respiration and hemodialysis in addition to
the provision of alternative metabolism of ammonia. Preventing severe urea
cycle disorders means that these levels are not reached in a patient treated
with the method of the present invention and later diagnosed with a urea
Moderate urea cycle disorders are characterized by plasma ammonia levels
less than about 500 micromoles/dL and may not require such aggressive
therapy. Thus, detection of hyperammonemia is most important for early
diagnosis and effective treatment. Typically associated with this increase
in ammonia buildup are acute episodes of vomiting, lethargy, convulsions and
abnormal liver enzyme levels. Exposure to high levels of plasma ammonia is
fatal typically following a period of lethargy, convulsions and coma. Even
treated, protracted severe hyperammonemia leads to mental and physical
For fetuses at risk, antenatal diagnosis is available by a number of
methods, particular to each disease, including enzyme analysis of
fibroplasts cultured from aminocytes, in utero liver biopsy, and DNA
techniques. All of these disorders respond to some degree to restriction of
protein intake. Acute episodes are usually precipitated by an increased
protein intake, an infection or any incident that leads to a negative
nitrogen balance. Treatment requires a restriction of dietary protein intake
and activation of other pathways of waste nitrogen synthesis and excretion.
Organic Acid Metabolic Disorders
The disorders of propionate metabolism, methylmalonic acidemia (MMA) and
propionic acidemia (PA), are the most common disorders of organic acid
metabolism. These disorders usually present in the neonatal period or early
infancy with vomiting, lethargy and metabolic acidosis, which may progress
to coma and death. The mainstay of treatment of PA and MMA is a diet
restricted in isoleucine, methionine, threonine, and valine. An inadequate
isoleucine, methionine, threonine and valine intake leads to poor growth
with chronic malnutrition, a serious complication of the organic acidemias.
Propionic acidemia (PA) is a deficiency or inactivity of propionylcoenzyme A
carboxylase and results in the accumulation of propionyl-coenzyme A and
propionic acid. Clinically, patients present with vomiting, dehydration,
lethargy and hypotonia in early infancy and are found to have ketonuria and
metabolic acidosis. Severe PA is characterized by plasma propionic acid
concentration of about 540 micromoles/dL, a value that is about 100 times
more than the normal value. Normal dietary protein is toxic to these
patients; toxicity is caused by the presence of excess metabolites of the
amino acids: isoleucine, methionine, threonine and valine. Preventing severe
PA means that these levels are not reached in a patient treated with the
method of the present invention and later diagnosed with PA.
After diagnosis, infants with this disorder respond well to dietary
restrictions of isoleucine, methionine, threonine and valine particularly in
the presence of adequate energy and protein equivalent.
Methylmalonicacidemia (MMA) results from an accumulation of methylmalonyl
coenzyme A and methylmalonic acid as a result of inactivity of one of two
enzymes sites: conversion of methylmalonic A to succinyl coenzyme A by
methylmalonyl coenzyme A mutase or enzymes involved in the synthesis of
adenosylcobalamin. As with PA, patients with MMA generally present with
vomiting, dehydration, lethargy and hypotonia in early infancy and are found
to have ketonuria and metabolic ketoacidosis.
Severe MMA is characterized by:
about <6.9 blood pH values
about <5 mEq/L plasma bicarbonate concentration; and about >290
micromoles/dL plasma methylmalonate concentration.
Preventing severe MMA means that these levels are not reached in a patient
treated with the method of the present invention and later diagnosed with
After diagnosis, about half of the patients having this metabolic defect
have responded to the administration of large amounts of vitamin B12. The
B12 responsive type is due to a defect in the metabolism of 5'
deoxyadenosyl-B12, while the B12 non-responsive type is the result of an
alteration in the methylmalonyl-coenzyme A mutase.
Post-diagnosis treatment consists of restricting isoleucine, methionine,
threonine and valine intakes and alkali therapy for the episodes of
acidosis. Typically nutritional support requires severe limitation of the
recognized propionate precursor amino acids: isoleucine, valine, methionine
and threonine. Catabolism of odd-chain fatty acids, cholesterol and
bacterial fermentation in the gut are also recognized as sources of
propionate, and catabolism of thymine as a source of methylmalonate
MS/MS technology is used for newborn screening of organic acid disorders. In
addition to PA and MMA, other organic acid disorders, such as
2-methylbutyryl coenzyme A dehydrogenase deficiency,
3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency (HMG),
3-methylcrotonyl coenzyme A carboxylase deficiency, 3-methylglutaconyl
coenzyme A hydratase deficiency, 5-oxoprolinuria, glutaric academia type I,
isobutyryl coenzyme A dehydrogenase deficiency, isovaleric academia, malonic
aciduria, mitochondrial acetoacetyl coenzyme A thiolase deficiency, and
multiple carboxylase deficiency, can be detected by this method. However,
severe metabolic deterioration due to ketoacidosis and hyperammonemia during
the early newborn period is usually seen in PA and MMA.
The time of onset and the severity of illness of the metabolically abnormal
infant after birth are dependent on the nature of metabolic block and the
amount of available amino acids and protein. MSUD and other branched chain
amino acid disorders accumulate .alpha.-ketoacids derived from BCAA, such as
leucine, isoleucine, and/or valine. On the other hand, urea cycle disorder
is related to the metabolism of almost all amino acids, leading to the
accumulation of glutamine, the precursor of ammonia.
The accumulation of propionic acid and methylmalonic acid is mainly through
the oxidation of isoleucine, valine, methionine, and threonine, causing
profound acidosis. Unless, there is a means to activate the deficient enzyme
activity or provide an alternative pathway, the accumulation of metabolites
is extremely fast leading to the sudden development of severe hyperammonemia
and/or metabolic acidosis. Such rapid development of metabolite accumulation
is caused by transamination of amino acids, which is closely correlated with
the amount of protein intake. For this reason, the prevention and long-term
therapeutic measures of recurrent life-threatening hyperammonia and
ketoacidosis are dependent on protein restriction.
Method of Testing for Inborn errors of Metabolism
With the exception of few disorders, most states perform the screening study
for each infant. Typically, the specimen is collected approximately 24 hours
after birth. The result of the studies is available within approximately two
weeks after the test.
The infant formula of the present invention contains (a) protein (b)
carbohydrate, (c) fat and (d) vitamins and minerals.
The infant formula of the present invention contains "a minimum level of
protein required for normal growth," which is a level of protein up to about
1.8 grams protein per 100 kcal (or about 1.22 g protein per 100 ml) of a
composition having 20 kcal per ounce. Preferably, the level of protein is
between about 1.3 and about 1.8 grams protein per 100 kcal (or about 0.9 to
about 1.22 g protein per 100 ml) of a composition having 20 kcal per ounce.
Most preferably, the level of protein is between about 1.3 and about 1.6
grams protein per 100 kcal (or about 0.9 to about 1.08 g protein per 100 ml)
of a composition having 20 kcal per ounce.
The protein can be any supplied in any conventional form such as casein,
salts of casein (e.g. potassium caseinate), whey protein concentrate,
soybean protein isolate, cow's milk protein, or hydrolyzed whey, or soy
protein. Preferably whey and casein are used. Preferably the whey: casein
ratio is 60:40 and 70:30. The whey can be prepared to have reduced
allergenicity using conventional techniques such as described in U.S. Pat.
No. 4,879,131. The whey can also be demineralized for example by
electrodialysis or ultrafiltration.
The formula of the present invention provides approximately 40-50% of its
total non-protein calories as carbohydrate. The source of carbohydrate can
be supplied in any conventional form including both simple and complex
forms. Preferably, the carbohydrate is provided in simple form. Simple
carbohydrates include lactose, sucrose, and corn syrup solids. Complex
carbohydrates include starches. Most preferably, the source of carbohydrate
is lactose. Alternatively, glucose or sucrose can be used.
The formula of the present invention contains 45-55% of its total calories
as fat. The fat can be supplied in any conventional form including saturated
fats, monounsaturated fats (MUFA), polyunsaturated fats (PUFA) or a mixture
thereof. Preferably the fat is provided as 1/3 saturated fat, 1/3 MUFA and
1/3 PUFA. Saturated fats include butyric, valeric, caproic, caprylic,
decanoic, lauric, myristic, palmitic, steraic, arachidic, behenic and
lignoceric. MUFAs include palmitoleic, oleic, claidic, vaccenic and erucic.
PUFAs include linoleic, .alpha.-linolenic (18:3), .gamma.-linoleic (1 8:2),
aracadonic (20:4), eicosopenanoate (20:5) and decosodexanoic (22:6).
Preferably, PUFA is supplied as a .alpha.-linolenic and linoleic.
An exemplary formulation includes:
Preferred source Amount
Protein Cow milk protein and 1.3-1.6 g/100 kcal
Fat Cow milk (lipids), soy or 3.0-4.0 g/100 ml
Carbohydrate Cow milk (lactose), 7.0-10.0 g/100 ml
glucose or sucrose.
Results of Treatment
The present invention postpones the onset of the infantile type acute
hyperammonemia and metabolic acidosis and the onset experienced is a less
severe degree compared with full-blown biochemical and clinical
abnormalities. Typically, the severity is reduced to a level such that the
metabolically abnormal infant is capable of responding to treatment with
medical foods for use in the nutritional support of an infant having the
inherited metabolic disorder with or without other interventions. The
present invention further prevents irreversible damage, such as permanent
damage of the central nervous system mental retardation, coma and death, to
undiagnosed metabolically abnormal infants.
Claim 1 of 8 Claims
What is claimed is:
1. A method of reducing severity and delaying onset of hyperammonemia and
metabolic acidosis in an infant having an inherited metabolic disorder
comprising administering to a newborn during a time prior to diagnosis of
the inherited metabolic disorder a composition comprising about 20 kcal per
ounce and up to about 1.8 g protein per 100 kcal of said composition.
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