o r s o f

r n e rr
In b o m
ta b o l i s
m e

Inborn errors of metabolism –

Phenylketonuria,

Galactosemia,

Maple Syrup Urine Disease,

Glycogen Storage Disease

Inborn errors of metabolism (IEM) are conditions caused by the genetic
errors related to :

synthesis,

metabolism,

transport or

storage of biochemical compounds.

The metabolic error usually results in the accumulation or deficiency of a
specific metabolite. These disorders are individually rare, but collectively
common, and manifest at any time from the fetal life to old age.

Early recognition of signs and symptoms, prompt evaluation and
management results in optimal outcome.

Genetic metabolic disorders are inherited traits - result in the absence or reduced activity of a
specific enzyme or cofactor necessary for optimal metabolism.

Most genetic metabolic disorders are inherited as autosomal-recessive traits.

The treatment for many metabolic disorders is MNT, with intervention specific to the disorder.

The goals of MNT are :

to maintain biochemical equilibrium for the affected pathway,

provide adequate nutrients to support typical growth and development, and

support social & emotional development.

Nutrition interventions are designed to circumvent the missing or inactive enzyme by :

(1) restricting the amount of substrate available,

(2) supplementing the amount of product,

(3) supplementing the enzymatic cofactor, or

(4) combining any or all of these approaches.
Newborn screening
Inborn errors of metabolism (IEM) are a heterogeneous group of
genetic disorders that cause significant neonatal and infant mortality.
Expanded newborn screening which detects these disorders at birth
is the standard preventive strategy in most countries. Prospective
studies to evaluate the impact of these in the Indian population are
lacking. The imminent need to address this lacuna warrants a
review of available pan India data, as well as efforts for a carefully
conducted prospective assessment of the burden of IEM.

The onset of illness could be either sudden, with Non-
specific physical findings. The course may be recurrent
and ep1sodic, and response to supportive therapy is
rapid

Whereas In some disorders , the onset is gradual with
slow progression. They usually have characteristic
findings that enable a specific clinical diagnosis.

The diagnosis of IEM is often delayed, and requires a
high index of suspicion. Symptoms are often nonspecific,
leading to evaluation for other disorders.

Laboratory Investigations



Metabolic screening includes measurement of blood
levels of glucose, electrolytes, lactate, pH, bicarbonate
and ammonia.
 
Phenylketonuria (PKU)

Phenylketonuria (PKU) -

inborn error of amino acid (AA) metabolism

caused by deficient activity of the enzyme phenylalanine hydroxylase (PAH), which is needed to
convert the essential AA phenylalanine (phe) to tyrosine.

Phenylalanine Requirement:

1-5 months: 47-90mg/kg

6-12 mo: 25-47mg/kg

Upto 10yrs:200-500mg/day(More phenylalanine (>800 mg) is required in the absence of tyrosine).

Tyrosine

1-5 mo: 60-80mg/kg

6-12 mo: 40-60mg/kg

Upto 10yrs-25-85 (mg/kg)

Total phenylalanine plus tyrosine should be considered in the prescription because most
phenylalanine is converted to tyrosine.

PKU probands and normal subjects have similar nitrogen requirements, though the WHO-defined
protein requirement for the PKU diet is higher than recommendations for healthy people because
the bioavailability of amino acids mixtures is not equivalent to that of natural protein (FAO-WHO
1985-91),

Without the enzyme - buildup can develop when a person with PKU
eats foods that contain protein or eats aspartame, an artificial
sweetener. This can eventually lead to serious health problems.


For the rest of their lives, people with PKU — babies, children and
adults — need to follow a diet that limits phenylalanine, which is found
mostly in foods that contain protein.

Prognosis and outcome depend strongly on the age at which the
diagnosis is made and treatment is introduced, but also on the type of
mutation. Because of evidence that early ending of treatment might
impair later neuropsychological performance, the treatment of PKU is
recommended for life

newborn screening programs for PKU(1960s) with initiation of a low-
phe diet soon after birth -helped PKU individuals with cognitive ability in
the normal range.

The biggest challenge to living with PKU- need for lifelong adherence to
the highly restrictive low-phe diet supplemented with an AA formula .

studies show significant differences in performance and intelligence in
children and neurologic function in adults who discontinue the low-phe
diet compared with those who remain on diet . Also, infants born to
women with poorly controlled PKU are at risk for congenital
malformations

Thus, a low-phe diet remains the cornerstone for lifelong treatment of
PKU.

Symptoms
PKU signs and symptoms can be mild or severe and may include:



A musty odor in the breath, skin or urine, caused by too much phenylalanine in the body

Neurological problems that may include seizures

Skin rashes (eczema);Fair skin and blue eyes, because phenylalanine can't transform into melanin — the
pigment responsible for hair and skin tone

Abnormally small head (microcephaly)

Hyperactivity

Intellectual disability;Delayed development

Behavioral, emotional and social problems

Psychiatric disorders



The severity of PKU depends on the type.



Classic PKU. The most severe form of the disorder is called classic PKU. The enzyme needed to convert
phenylalanine is missing or severely reduced, resulting in high levels of phenylalanine and severe brain
damage.

Less severe forms of PKU. In mild or moderate forms, the enzyme retains some function, so
phenylalanine levels are not as high, resulting in a smaller risk of significant brain damage.

But most children with the disorder still require a special PKU diet to prevent intellectual disability and other
complications.
 causes

A defective gene (genetic mutation) causes PKU, which can
be mild, moderate or severe. In a person with PKU, this
defective gene causes a lack of or deficiency of the enzyme
that's needed to process phenylalanine, an amino acid.

This buildup of phenylalanine results in damage to nerve
cells in the brain.

Risk factors:

Family history-two parents who are carriers of the disorder,

Being of certain ethnic descent
 complications

Untreated PKU can lead to:



Irreversible brain damage and marked intellectual
disability beginning within the first few months of life

Neurological problems such as seizures and tremors

Behavioral, emotional and social problems in older
children and adults

Major health and developmental problems

Prevention & treatment
Follow a low-phenylalanine diet. And Consider genetic counseling.



The main treatment for PKU includes:



A lifetime diet with very limited intake of protein, because foods with protein contain
phenylalanine

Taking a PKU formula — a special nutritional supplement — for life to make sure
you get enough essential protein (without phenylalanine) and nutrients that are crucial
for growth and general health

A safe amount of phenylalanine differs for each person with PKU and can vary over
time. In general, the idea is to consume only the amount of phenylalanine that's
necessary for normal growth and body processes, but no more. Your doctor can
determine a safe amount through:

Regular review of diet records, growth charts and blood levels of phenylalanine

Frequent blood tests that monitor phenylalanine levels as they change over time,
especially during childhood growth spurts and pregnancy

Other tests that assess growth, development and health

 treatment

Foods to avoid

Special formulas

Neutral amino acid therapy- This supplement may block
some absorption of phenylalanine. This may be a
treatment option for adults with PKU(powder or tablet
form)

PKU medication-(sapropterin -Kuvan) -works by
increasing tolerance to phenylalanine. used in combination
with a PKU diet. But it doesn't work for everyone with PKU.
 MNT

main goals of treatment for PKU are to maintain the blood Phe concentration
within safe limits (i.e. 120– 360 mmol/L; for pregnant women 120–240 mmol/L), to
prevent mental retardation, and to ensure normal growth and normal life with good
health through adulthoodNutritional management in the form of a low-phe diet is
essential to achieve metabolic control of phe levels and allow normal development of
the brain in those with PKU.

it is known that high blood Phe concentrations are neurotoxic, mainly because of
the inhibitory action of Phe on the transport of free L-amino acids (leucine,
isoleucine, valine, tyrosine, tryptophan and lysine) necessary for protein and
neurotransmitters synthesis (dopamine and serotonin)

The key development of a source of dietary protein that was free of phe was
achieved by acid hydrolysis of casein followed by treatment with activated
charcoal to remove phe.

Today, the major source of dietary protein for those with PKU consists of mixtures
of synthetic AA devoid of phe and a small amount of dietary protein from fruits
and vegetables to provide phe.

Goal of nutritional management for those with PKU is to
maintain plasma phe concentrations that support optimal
growth, development, and mental functioning while
providing a nutritionally complete diet.

European & US countries consensus that any newborn
infant with a plasma phe concentration of >400–600 μM
should be started on a low-phe diet as soon as possible,
which is easily achieved in infancy and compatible with
limited breastfeeding.


The low-phe PKU diet (in classical PKU, <500 mg phe per day )
requires two interrelated dietary modifications to achieve metabolic
control of plasma phe concentrations.

First, natural foods are severely restricted to limit protein intake yet
provide adequate amounts of phe, an essential AA. This generally
includes elimination of all sources of animal protein, legumes and nuts,
as well as limited intake of bread, pasta, rice and some vegetables.
Low-protein bread and pasta products made from starch are used to
provide needed energy and to increase variety.

Second, consumption of an AA-based, phe-free formula (600–900 ml
per day) or AA medical food is needed to provide adequate protein,
vitamins, minerals and energy due to the restriction in natural foods.
 Newer strategies

Peptides-Among the peptides, glycomacropeptide (GMP) is the only
naturally occurring protein that is phenylalanine-free, so that this
characteristic makes GMP an excellent source of protein for people with
PKU

Beyond the control of plasma phenylalanine levels, new emerging
issues indicate that early nutrition may have longlasting effects in PKU
patients. Human milk and breast feeding, and early amino acid and LC-
PUFA supply, seem to have independent effects on development. New
formulas, Phe-free peptides, and ‘modulated’ amino acid preparations
might help in preventing nutritional deficiencies and imbalances,with the
ultimate aim of improving growth. New strategies—such as BH4
(tetrahydrobiopterin )supply—need to be optimized with regard to
targets, patients and expected outcomes.

the diet of PKU patients gives a low intake of long-
chain polyunsaturated fatty acids (LC-PUFAs) such as
arachidonic acid (AA) and docosahexaenoic-acid
(DHA), which are present only in food from animal
sources . Therefore, PKU patients must rely on the
endogenous synthesis of LC-PUFAs from their
precursors, the content of which also is often
suboptimal in dietary products for patients with PKU,
particularly that of α-linolenic acid (ALA), the
precursor of DHA

Tyrosine - essential AA for those with PKU given the
inability to normally hydroxylate phe to tyrosine.
Tyrosine is a precursor for thyroxine, catecholamines
and melanin, and plasma levels should be monitored in
parallel with phe as many patients will show low tyrosine
levels. However, tyrosine supplementation alone does
not correct the PKU phenotype Although tyrosine is
provided in large quantities in AA formulas, it is very
insoluble and individuals may not receive enough if they
do not shake their formula before consumption
 Monitoring Phe Concentrations

Frequent monitoring of plasma concentrations of phe and tyrosine in
relation to phe intake, often provided by a 3-day record of food intake
preceding blood sampling, is needed to adjust the dietary prescription
for phe.

When the growth rate is at its peak, as in early infancy and during the
prepubertal and pubertal growth spurts, phe needs will be high relative
to body mass and will then decline as the growth rate slows,

The phe ingested should maintain the 2- to 4-hour postprandial plasma
phe concentration within the recommended target range During
infancy, weekly adjustments in the phe prescription may be needed
based on growth and assessment of plasma phe concentrations.
Subsequently, phe is assessed once or twice monthly
 counselling

Knowing the facts about PKU

Learn from other families.

help with menu planning

Let child help manage his or her diet as early
as possible

Talk to teachers and other staff in child's school.

Maintain a positive food attitude
 Galactosemia

Galactosemia- elevated level of plasma galactose-1-
phosphate combined with galactosuria,- autosomal-
recessive metabolic disorders: galactokinase deficiency
and galactose1-phosphate uridyltransferase (GALT)
deficiency,

Illness generally occurs within the first 2 weeks of life.
Symptoms - vomiting, diarrhea, lethargy, failure to thrive,
jaundice, hepatomegaly, and cataracts. may be
hypoglycemic & susceptible to infection from gram-negative
organisms- may cause septicemia- death, if not treated.
 Pathphysiology

Galactosemia – caused due to disturbance in
conversion of galactose to glucose because of
the absence or inactivity of one of the enzymes.

Enzyme deficiency causes an accumulation of
galactose, or galactose& galactose-1-
phosphate, in body tissues.

 Medical Treatment

If diagnosis & therapy are delayed, intellectual
disability can result

With early diagnosis and treatment,physical and
motor development proceed normally; but
intellectual achievement gets affected(have IQs of
85 - 100, visual-perceptual and speech difficulties,
and problems with executive function .

Ovarian failure affects approximately 75% to 95% of
women with galactosemia
 Medical Nutrition Therapy

Galactosemia is treated with lifelong galactose restriction.

Galactose is required for production of galactolipids & cerebrosides( produced
by alternative pathway if galactose is omitted from the diet). Galactose
restriction mandates strict avoidance of all milk and milk products and lactose
containing foods because lactose is hydrolyzed into galactose and glucose.
Effective galactose restriction requires careful reading of food product labels .

Milk is added to many products, and lactose often appears in the coating of the
tablet form of medications.

Infants with galactosemia are fed soy-based formula .

Medical opinions differ about the intensity and duration of treatment . Many
centers eliminate galactose from the diets of these children for the first year of
life; other centers do not.
Maple Syrup Urine Disease


(MSUD), or branched-chain ketoaciduria- results
from a defect in enzymatic activity- branched-
chain alpha-ketoacid dehydrogenase complex.

An autosomal-recessive disorder.

Within 4 or 5 days after birth ; infants show poor
feeding, vomiting, lethargy, and periodic
hypertonia, characteristic sweet, malty odor from
the urine and perspiration obseved by first week.
 Pathophysiology

The decarboxylation defect of MSUD prevents
metabolism of the branched-chain amino acids
(BCAAs) leucine, isoleucine,and valine. Leucine
metabolism significantly more abnormal than
other two BCAAs- reason not known

Precise mechanism for the complete
decarboxylase reaction and the resultant
neurologic damage.
 Medical Treatment(MSUD)

Diagnosis before 7 days of age and long-term metabolic control are
critical factors in long-term normalization of intellectual development. If
untreated; leads to- acidosis, neurologic deterioration, seizures, and
coma, proceeding eventually to death.

Management of acute disease - requires peritoneal dialysis and
hydration

Reasonable growth and intellectual development in the normal-to-low-
normal range have been described.

Maintenance of plasma leucine conc.(infants & preschool
children)close to physiologically normal as possible-.If > 10 mg/dl (760
mol/L) -- associated with alpha-ketoacidemia & neurologic symptoms.
 Medical Nutrition Therapy(MSUD)

Nutrition therapy requires very careful monitoring of blood concentrations of
leucine, isoleucine, and valine as well as growth and general nutritional
adequacy.

Several formulas specifically designed for the treatment of this disorder are
available to provide a reasonable amino acid and vitamin mixture.

These generally are supplemented with a small quantity of standard infant
formula or cow’s milk to provide the BCAAs needed to support growth and
development.

BCAAs may be introduced gradually into the diet when plasma leucine
concentrations are decreased sufficiently .

Clinical relapse often related to infection; & If plasma leucine concentration
increases rapidly during illness, BCAAs should be removed from the diet
immediately and intravenous therapy can be started.
 Glycogen Storage Disease(GSD)


GSD- inability to metabolize glycogen to glucose.

Number of possible enzyme defects along the
pathway. Common types-GSD types I and III.

Symptoms - poor physical growth, hypoglycemia,
hepatomegaly, and abnormal biochemical
parameters, (chol. and TG).

Advances in treatment - improve QOL for
affected children
 Pathophysiology(GSD)


GSD type Ia (25% of GSDs)- defect -enzyme glucose1-6-phosphatase, impairs

-formation of new glucose (gluconeogenesis) &

- breakdown of glycogen from storage (glycogenolysis).

The affected person is unable to metabolize glycogen stored in the liver.

Severe hypoglycemia can result and cause irreparable damage.

GSD III or debrancher enzyme deficiency-Amylo-1, 6-glucosidase deficiency -
prevents glycogen breakdown beyond branch points.

- glycogenolysis is inefficient(as in GSD Ia); but

-gluconeogenesis is amplified to help maintain glucose production.

GSD III symptoms - usually less severe and range from hepatomegaly to
severe hypoglycemia
 Medical treatment(GSD)

The outcome of treatment has been good- severe hypoglycemic
episodes decreased;improved physical growth , liver size is
decreased. The risk of progressive renal dysfunction is not entirely
eliminated by current treatment, but liver transplantation for some
types of GSD (e.g., type Ib) is sometimes an option.

Treatment protocols -still evolving; include various kinds of
carbohydrates at various doses during the day and night. Individual
tolerance, body weight, state of health, ambient temperature, and
physical activity are important considerations when designing the
specific pattern of carbohydrate administration.

The goal is -normalization of blood glucose
 MNT(GSD)

The rationale for intervention- maintain plasma glucose in a normal
range & prevent hypoglycemia.

Administration of raw cornstarch (e.g., a slurry of cornstarch mixed
with cold water) at regular intervals and a high–complex
carbohydrate, low-fat dietary pattern are advocated to prevent
hypoglycemia. Some require glucose polymers( via continuous-drip
gastric feedings) to prevent hypoglycemic episodes during the night.

Dose of cornstarch individualized; -1.6 to 2.5 g/kg at 4- to 6-hour
intervals are generally effective for young children with GSD

Iron supplementation required (as cornstarch interferes with iron
absorption).
 ROLE OF NUTRITIONIST
IN
GENETIC METABOLIC DISORDERS

The role of the pediatric nutrition specialist in the treatment
of metabolic disorders is a complex one that requires
expertise in MNT for the specific disorder. Preparation and
competency requires access to detailed information about
the disorders and treatment modalities. A family-centered
approach, knowledge of feeding-skill development, and
understanding of behavior modification techniques, as well
as the support and counsel of a team of health care
providers involved in the care of the patient, are also
required. Nutrition intervention is often a lifelong
consideration
 Intervention Objectives -
Nutritionist -
Treatment of Genetic Metabolic Disorders
The Dietician has - major role in therapy and planning for each child.



It includes:

gathering food intake data from the family,

assessing the adequacy of the child’s intake,

working with the family to incorporate appropriate ways to monitor the
restricted food intake pattern.

The child with a metabolic disorder often presents with a wide range of
concerns- unstable biochemical markers, failure to gain weight/excessive
weight gain, difficulty adhering to the diet, and behaviors.

Thus managing a child with a metabolic disorder requires input from the
entire health care team