INBORN ERRORS of METABOLISM

Phenylketonuria (PKU)

- is an inborn error of metabolism that results from the absence of a liver enzyme, phenylalanine hydroxylase. It is an inherited
autosomal recessive trait that causes negative impact on development and mental retardation.Phenylalanine hydroxylase enzyme is
responsible for the conversion of phenylalanine (an essential amino acid) to tyrosine. The nonessential amino acid, tyrosine, is a
significant element for some neurotransmitters such as dopamine, norepinephrine, epinephrine and serotonin. It is also essential
in the production of melanin and function of the hormone regulating organs such as thyroid, pituitary, and adrenal glands.

Consequences of absent liver enzyme in children with PKU would result to deficient tyrosine leading to the following conditions:

• Absence of serotonin, dopamine and epinephrine

Result: Faulty nerve (Nervous System) transmission

Neurotransmitters communicate impulses to the nerve cells. Lack of tyrosine would lead to deterioration of this function. Mood
regulation is also connected to the presence of these chemicals (dopamine, serotonin, and epinephrine); therefore, alteration of
one’s disposition and temperament will be expected.

• Deficient Melanin levels

Result: Unusual skin color

Melanin is responsible for skin pigmentation. Deficient levels of melanin lead to a very fair complexion, a light blond hair and
blue eyes.

• Hyposecretion of thyroid hormones

Result: Permanent brain damage (Mental Retardation) and developmental delay

Thyroid glands are located at the throat that comprises the two lateral masses on each side of the trachea. Before the two active
thyroid hormones are produced, a process known as iodide trapping (iodide ion is concentrated within the thyroid) occurs. Then
iodide is dissolved inside the follicular cells of the thyroid to become iodine and later released as a colloid. Colloids contain
thyroglobulins which are made up of the amino acid tyrosine. Iodide when combined with tyrosine produces Monoiodotyrosine
(MIT) and Diiodotyrosine (DIT). Conversion of MIT and DIT would form the two active thyroid hormone, triiodothyronine
(T3) and Thyroxine (T4). These hormones are stored in the follicular cells until needed. T3 and T4 are primarily responsible for
cellular metabolism affects nearly all cells in the body. They play a vital role for normal development to occur.

In PKU, no Monoiodotyrosine (MIT) and Diiodotyrosine (DIT) is formed due to absence of tyrosine. Production of T3 and T4
would be inevitable causing decrease basal metabolism, cessation of cognitive and physical development. Most children with
PKU are cognitively challenged having an IQ of less than 20.

• Increase Phenylalanine levels

Result: Mousy urine odor

Phenylalanine levels increase due to the absence of the liver enzyme. The end product of phenylalanine metabolism is
phenylpyruvic acid (a keto acid). The by-product spills into the urine that gives it a strong “mousy” or “musty” odor that often
spreads through the entire body of the infant or child. This is the reason why the disorder is called phenylketonuria (meaning there
is phenylpruvic or keto acid in the urine)

Glucose-6-Phosphate Deficiency

Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs most often in males. This condition mainly
affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an
enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red
blood cells is called hemolysis.

The most common medical problem associated with glucose-6-phosphate dehydrogenase deficiency is hemolytic anemia, which
occurs when red blood cells are destroyed faster than the body can replace them. This type of anemia leads to paleness, yellowing
of the skin and whites of the eyes (jaundice), dark urine, fatigue, shortness of breath, and a rapid heart rate. In people with
glucose-6-dehydrogenase deficiency, hemolytic anemia is most often triggered by bacterial or viral infections or by certain drugs
(such as some antibiotics and medications used to treat malaria). Hemolytic anemia can also occur after eating fava beans or
inhaling pollen from fava plants (a reaction called favism).

Glucose-6-dehydrogenase deficiency is also a significant cause of mild to severe jaundice in newborns. Many people with this
disorder, however, never experience any signs or symptoms.
Galactosemia

Galactosemia is an inherited carbohydrate metabolism disorder. This metabolic disorder is characterized by the abnormal levels
of galactose in the blood (galactosemia) and in the urine (galactosuria). People with this disorder are unable to breakdown the
simple sugar galactose to glucose.

This inborn error of metabolism occurs 1 in every 60,000 births. Higher incidence rate is noted in Ireland with about 1 case in
every 20,000 population. It is less common in Asian people.

Galactosemia follows an autosomal recessive mode of inheritance that is typified by the absence or deficiency of any of the three
enzymes that are involved in galactose to glucose conversion which are:

• Galactokinase – uncommon
• Galactose 1-phosphate uridyltransferase or GALT – most common deficiency
• Uridine diphosphate (UDP)-galactose4-epimerase or GALE – uncommon

Galactose, a type of sugar, has to be converted to glucose before it can be used by the body. Lactose, the sugar found in milk, is
normally broken down into galactose and glucose.

1. Galactokinase (GALK) converts galactose to galactose 1-phosphate.

2. Galactose 1-phosphate uridyltransferase (or GALT) converts galactose 1-phosphate to UDP galactose. It also converts UDP
glucose to glucose 1-phosphate.
3. Finally, Uridine diphosphate (UDP)-galactose 4-epimerase (or GALE) converts UDP galactose to UDP glucose to be used
by the body.

To summarize, the order of galactose conversion in its metabolic pathway in relation to the enzymes it encounters starts with
GALK then GALT and finally GALE.

Types of Galactosemia
Type 1 – characterized by absence of the liver enzyme GALT. It is termed as the classic galactosemia. This is the most common
type. People with absent or deficient GALT have intolerance to galactose.
Type 2 – characterized by the absence of the enzyme Galactokinase (GALK). It is called as galactokinase deficiency.
Type 3 – characterized by absence of the enzyme GALE. This form of galactosemia is termed as UDP-Galactose-4-epimerase
deficiency.
Pathophysiology

Absence or deficiency of galactose 1-phosphate uridyltransferase (GALT) prevents the conversion of galactose into glucose.
When an infant or neonate is given milk (formula milk or breast milk), the substances made from galactose builds up in the
bloodstream (galactosemia) and spills into the urine (galactosuria). These can cause severe damage to the eyes, kidneys, liver and
brain.

Diagnosis

Beutler’s test – a screening test used to analyzed the cord blood if a child is known to be at risk for the disorder.

Newborn Screening Test – a heel puncture test done in newborns.

Clinical Manifestations

The symptoms begin to appear when the neonate is started on formula feeding or breastfeeding.

• Lethargy
• Hypotonia
• Diarrhea
• Vomiting

The symptoms start abruptly and develop rapidly leading to further manifestations:

• Hepatomegaly – liver enlarges

• Persistent jaundice
• Bilateral cataracts
• Brain damage
• Ascites – fluid in the abdomen
• Galactosuria – galactose in urine

Untreated neonates may die by 3 days of age. Those who survived beyond the untreated 3 days may have bilateral cataracts and
will be cognitively challenged.

Management

Early detection prevents fatal complications. Timely identification and management of galactosemia prevents brain damage. Any
neurologic or cataract damage present before the treatment will persist.

• Galactose-free diet for life

• Milk substitute such as casein hydrolysates (Nutraminogen)

Congenital Hypothyroidism

Neonatal hypothyroidism is decreased thyroid hormone production in a newborn. In very rare cases, no thyroid hormone is
produced.If the baby was born with the condition, it is called congenital hypothyroidism. If it develops soon after birth, it is
referred to as hypothyroidism acquired in the newborn period.

Hypothyroidism in the newborn may be caused by:

• A missing or abnormally developed thyroid gland
• Pituitary gland's failure to stimulate the thyroid
• Defective or abnormal formation of thyroid hormones
Incomplete development of the thyroid is the most common defect and occurs in about 1 out of every 3,000 births. Girls are
affected twice as often than boys.

Symptoms
Most affected infants have few or no symptoms, because they only have a mild decrease in thyroid hormone production. However,
infants with severe hypothyroidism often have a distinctive appearance. Symptoms may include:
• Puffy-appearing face
• Dull look
• Thick, protruding tongue

This appearance usually develops as the disease gets worse. The child may also have:
• Dry, brittle hair
• Low hairline
• Jaundice
• Poor feeding
• Choking episodes
• Lack of muscle tone (floppy infant)
• Constipation
• Sleepiness
• Sluggishness
• Short stature

Exams and Tests

A physical exam may reveal:
• Abnormally large fontanelles (soft spots of the skull)
• Broad hands with short fingers
• Decreased muscle tone
• Growth failure
• Hoarse-sounding cry or voice
• Short arms and legs
• Widely separated skull bones

Blood tests will be done to check thyroid function. Other tests that may be done include:
• Thyroid scan
• X-ray of the long bones

Treatment
Early diagnosis is very important. Most of the effects of hypothyroidism are easily reversible.
Replacement therapy with thyroxine is the standard treatment of hypothyroidism. Once medication starts, thyroid blood tests are
regularly done to make sure levels are within a normal range.

Outlook (Prognosis)
Very early diagnosis generally results in a good outcome. Newborns diagnosed and treated in the first month or so generally
develop normal intelligence.
Untreated, mild hypothyroidism can lead to severe mental retardation and growth retardation. Critical development of the nervous
system takes place in the first few months after birth. Thyroid hormone deficiency may cause irreversible damage.

Possible Complications

• Mental retardation
• Growth retardation
• Heart problems

Congenital adrenal hyperplasia

In congenital adrenal hyperplasia (CAH), the adrenal gland is not producing enough cortisol and aldosterone but extremely
supplies androgen (masculinizing hormone) in the body. This is an autosomal recessive inherited gene can cause a large clitoris in
females, closed labial folds, no menses and breast development. The female baby at birth appears to have a penis with
undescended testes. In males, the genitals appear normal at birth but sexual precocity starts to occur by about 6 months where the
penis is enlarged and pubic hair grows early. Sterility also is a complication in boys as absence of spermatogenesis is noted.