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- 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 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.
a type of sugar. It is less common in Asian people.000 population. 3. Higher incidence rate is noted in Ireland with about 1 case in every 20. the sugar found in milk. Type 3 – characterized by absence of the enzyme GALE. It is termed as the classic galactosemia. the order of galactose conversion in its metabolic pathway in relation to the enzymes it encounters starts with GALK then GALT and finally GALE. Galactokinase (GALK) converts galactose to galactose 1-phosphate. Uridine diphosphate (UDP)-galactose 4-epimerase (or GALE) converts UDP galactose to UDP glucose to be used by the body. To summarize. Types of Galactosemia Type 1 – characterized by absence of the liver enzyme GALT. Lactose. People with absent or deficient GALT have intolerance to galactose. This is the most common type. This inborn error of metabolism occurs 1 in every 60.Galactosemia Galactosemia is an inherited carbohydrate metabolism disorder. 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. 1. It also converts UDP glucose to glucose 1-phosphate. . Finally. has to be converted to glucose before it can be used by the body. This metabolic disorder is characterized by the abnormal levels of galactose in the blood (galactosemia) and in the urine (galactosuria). 2. It is called as galactokinase deficiency. Galactose 1-phosphate uridyltransferase (or GALT) converts galactose 1-phosphate to UDP galactose.000 births. This form of galactosemia is termed as UDP-Galactose-4-epimerase deficiency. Type 2 – characterized by the absence of the enzyme Galactokinase (GALK). is normally broken down into galactose and glucose. People with this disorder are unable to breakdown the simple sugar galactose to glucose.
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. kidneys. These can cause severe damage to the eyes. no thyroid hormone is produced.Pathophysiology Absence or deficiency of galactose 1-phosphate uridyltransferase (GALT) prevents the conversion of galactose into glucose. it is called congenital hypothyroidism. liver and brain. 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 . If it develops soon after birth. Timely identification and management of galactosemia prevents brain damage. it is referred to as hypothyroidism acquired in the newborn period.If the baby was born with the condition. • • Galactose-free diet for life Milk substitute such as casein hydrolysates (Nutraminogen) Congenital Hypothyroidism Neonatal hypothyroidism is decreased thyroid hormone production in a newborn. Those who survived beyond the untreated 3 days may have bilateral cataracts and will be cognitively challenged. When an infant or neonate is given milk (formula milk or breast milk). In very rare cases. Clinical Manifestations The symptoms begin to appear when the neonate is started on formula feeding or breastfeeding. Any neurologic or cataract damage present before the treatment will persist. the substances made from galactose builds up in the bloodstream (galactosemia) and spills into the urine (galactosuria). • • • • 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. Management Early detection prevents fatal complications. Newborn Screening Test – a heel puncture test done in newborns.
Newborns diagnosed and treated in the first month or so generally develop normal intelligence. Sterility also is a complication in boys as absence of spermatogenesis is noted. thyroid blood tests are regularly done to make sure levels are within a normal range. The child may also have: • Dry. Replacement therapy with thyroxine is the standard treatment of hypothyroidism. The female baby at birth appears to have a penis with undescended testes. Most of the effects of hypothyroidism are easily reversible. . In males. This is an autosomal recessive inherited gene can cause a large clitoris in females. Thyroid hormone deficiency may cause irreversible damage. the adrenal gland is not producing enough cortisol and aldosterone but extremely supplies androgen (masculinizing hormone) in the body. Girls are affected twice as often than boys. However. no menses and breast development. Other tests that may be done include: • Thyroid scan • X-ray of the long bones Treatment Early diagnosis is very important.Incomplete development of the thyroid is the most common defect and occurs in about 1 out of every 3. protruding tongue This appearance usually develops as the disease gets worse. 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. infants with severe hypothyroidism often have a distinctive appearance. Possible Complications • • • Mental retardation Growth retardation Heart problems Congenital adrenal hyperplasia In congenital adrenal hyperplasia (CAH). because they only have a mild decrease in thyroid hormone production. Outlook (Prognosis) Very early diagnosis generally results in a good outcome. Symptoms may include: • Puffy-appearing face • Dull look • Thick. Symptoms Most affected infants have few or no symptoms. closed labial folds. 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. Critical development of the nervous system takes place in the first few months after birth.000 births. Once medication starts. mild hypothyroidism can lead to severe mental retardation and growth retardation. Untreated.