Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH).

This enzyme is necessary to metabolize the amino acid phenylalanine ('Phe') to the amino acid tyrosine. When PAH is deficient, phenylalanine accumulates and is converted into phenyl pyruvate (also known as phenylketone), which is detected in the urine. Since its discovery, there have been many advances in its treatment. It can now be managed by the patient with little or no side-effects other than the inconvenience of managing the treatment. If, however, the condition is left untreated, it can cause problems with brain development, leading to progressive mental retardation, brain damage, and seizures. In the past, PKU was treated with a low-phenylalanine diet. Latter-day research now has shown that diet alone may not be enough to prevent the negative effects of phenylalanine levels. Optimal treatment involves lowering blood Phe levels to a safe range and monitoring diet and cognitive development. Lowering of phenylalanine levels to a safe range may be achieved by combining a low-phenylalanine diet with protein supplements. Maternal phenylketonuria For women affected with PKU, it is essential for the health of their child to maintain lowphenylalanine levels before and during pregnancy. Though the developing fetus may only be a carrier of the PKU gene, the intrauterine environment can have very high levels of phenylalanine, which can cross the placenta. The result is that the child may develop congenital heart disease, growth retardation, microcephaly and mental retardation. PKUaffected women themselves are not at risk from additional complications during pregnancy. In most countries, women with PKU that wish to have children are advised to lower their blood phenylalanine levels (typically to between 2 and 6 micromol/deciliter) before they become pregnant, and carefully control their phenylalanine levels throughout the pregnancy. This is achieved by performing regular blood tests and adhering very strictly to a diet, in general monitored on a day-to-day basis by a specialist metabolic dietitian. In many cases, as the fetus' liver begins to develop and produce PAH normally, the mother's blood phenylalanine levels will drop, requiring an increased phenylalanine intake to remain within the safe range of 2-6 micromol/dL. The mother's daily phenylalanine intake may double or even triple by the end of the pregnancy, as a result. When maternal blood phenylalanine levels fall below 2 micromol/dL, anecdotal reports indicate that the mothers may suffer adverse effects including headaches, nausea, hair loss, and general malaise. When low phenylalanine levels are maintained for the duration of pregnancy, there are no elevated levels of risk of birth defects compared with a baby born to a non-PKU mother. Babies with PKU may drink breast milk, while also taking their special metabolic formula. Some research has indicated that an exclusive diet of breast milk for PKU babies may alter the effects of the
Amberlee Peti 12.5

deficiency, though during breastfeeding the mother must maintain a strict diet to keep their phenylalanine levels low. More research is needed. US scientist have recently announced (June 2010) that they will be conducting thorough investigation on the mutation of genes in the human genome. Their top priority is Phenylketonuria as it has become increasingly common, due to the fact that sufferers often live past the age of sixty and often bear children (carriers of the recessive gene). Inheritance

Autosomal recessive An autosomal recessive disorder means two copies of an abnormal gene must be present in order for the disease or trait to develop. Inheriting a specific disease, condition, or trait depends on the type of chromosome affected (autosomal or sex chromosome). It also depends on whether the trait is dominant or recessive. A mutation in a gene on one of the first 22 nonsex chromosomes can lead to an autosomal disorder. Genes come in pairs. Recessive inheritance means both genes in a pair must be defective to cause disease. People with only one defective gene in the pair are considered carriers. However, they can pass the abnormal gene to their children. CHANCES OF INHERITING A TRAIT If you are born to parents who both carry an autosomal recessive change (mutation), you have a 1 in 4 chance of getting the malfunctioning genes from both parents and developing the disease. You have a 50% (1 in 2) chance of inheriting one abnormal gene. This would make you a carrier.
Amberlee Peti 12.5

In other words, if four children are born to a couple who both carry the gene (but do not have signs of disease), the statistical expectation is as follows:

One child is born with two normal genes (normal) Two children are born with one normal and one abnormal gene (carriers, without disease) One child is born with two abnormal genes (at risk for the disease)

Incidence The incidence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations. The illness is also more common in Italy and China, as well as in Yemeni populations. Screening and presentation Blood is taken from a two-week old infant to test for phenylketonuria PKU is normally detected using the HPLC test, but some clinics still use the Guthrie test, part of national biochemical screening programs. If a child is not screened during the routine newborn screening test (typically performed 6 14 days after birth, using samples drawn by heel prick), the disease may present clinically with seizures, albinism (excessively fair hair and skin), and a "musty odor" to the baby's sweat and urine (due to phenyl acetate, one of the ketones produced). In most cases, a repeat test should be done at approximately 2 weeks of age to verify the initial test and uncover any phenylketonuria that was initially missed. Untreated children are normal at birth, but fail to attain early developmental milestones, develop microcephaly (a condition of abnormal smallness of the head usually associated with mental retardation) , and demonstrate progressive impairment of cerebral function. Hyperactivity, EEG abnormalities and seizures, and severe learning disabilities are major clinical problems later in life. A "musty or mousy" odor of skin, hair, sweat and urine (due to phenylacetate accumulation); and a tendency to hypopigmentation and eczema are also observed. Metabolic pathways The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Metabolites include
Amberlee Peti 12.5

phenyl acetate, phenyl pyruvate and phenethylamine. Elevated levels of phenylalanine in the blood and detection of phenylketones in the urine is diagnostic. Phenylalanine is a large, neutral amino acid (LNAA). LNAAs compete for transport across the blood-brain barrier (BBB) via the large neutral amino acid transporter (LNAAT). If phenylalanine is in excess in the blood, it will saturate the transporter. Excessive levels of phenylalanine tend to decrease the levels of other LNAAs in the brain. However, as these amino acids are necessary for protein and neurotransmitter synthesis, phenylalanine buildup hinders the development of the brain, causing mental retardation. Diagnosis The Guthrie test, also known as the Guthrie bacterial inhibition assay, is a medical test performed on newborn infants to detect phenylketonuria, an inborn error of amino acid metabolism. Theory and method The Guthrie test is designed to detect elevated blood levels of the amino acid phenylalanine, using the ability of phenylalanine to facilitate bacterial growth in a culture medium with an inhibitor. A drop of blood is usually obtained by pricking the heel of a newborn infant in a hospital nursery on the sixth or seventh day of life (end of the first week). The blood is collected on a piece of filter paper and sent to a central laboratory. A small disk of the filter paper is punched out and placed on an agar gel plate containing Bacillus subtilis and B-2thienylalanine. Each gel holds 60-80 disks. The agar gel is able to support bacterial growth but the B-2-thienylalanine inhibits bacterial growth. However, in the presence of extra phenylalanine leached from the impregnated filter paper disk, the inhibition is overcome and the bacteria grow. Within a day the bacterial growth surrounding the paper disk is visible to the eye. The amount of growth, measured as the diameter of the colony, is roughly proportional to the amount of phenylalanine in the serum. The result is read by comparing the diameter of each sample disk's colony to the colonies of a series of reference disks with standard phenylalanine content included on each large plate.

Interpretation of results The Guthrie assay is sensitive enough to detect serum phenylalanine levels of 180-240 mol/L (3-4 mg/dL). In healthy normal people, phenylalanine levels are usually under 120 mol/L. Less than 10% of the positive results obtained by the screening program are confirmed as due to phenylketonuria (PKU). There are other metabolic diseases that can produce hyperphenylalaninemia (means elevated blood phenylalanine), but false positive results can also occur due to unexplained mild, transient elevations, prematurity, parenteral nutrition, or contamination of the filter paper specimen. False negative results can be produced by antibiotics in the blood sample. Misleadingly low results can also occur if a sample is taken too soon after birth, since phenylalanine levels rise steadily with age and protein feeding.

Amberlee Peti 12.5

The term "Guthrie test" is sometimes used in a broader sense to describe dried blood spot testing, which can be used to test for several other conditions. The filter cards are sometimes called "Guthrie cards". Treatment PKU patients must adhere to a special diet low in phenylalanine for at least the first 16 years of their lives. This requires severely restricting or eliminating foods high in phenylalanine, such as meat, chicken, fish, eggs, nuts, cheese, legumes, cow milk and other dairy products. Starchy foods such as potatoes, bread, pasta, and corn must be monitored. Infants may still be breastfed to provide all of the benefits of breastmilk, but the quantity must also be monitored and supplementation for missing nutrients will be required. Many diet foods and diet soft drinks that contain the sweetener aspartame must also be avoided, as aspartame consists of two amino acids: phenylalanine and aspartic acid. Supplementary infant formulas are used in these patients to provide the amino acids and other necessary nutrients that would otherwise be lacking in a low-phenylalanine diet. As the child grows up, these can be replaced with pills, formulas, and specially formulated foods. (Since phenylalanine is necessary for the synthesis of many proteins, it is required for appropriate growth but levels must be strictly controlled in PKU patients). In addition, tyrosine, which is normally derived from phenylalanine, must be supplemented. The oral administration of tetrahydrobiopterin (or BH4) (a cofactor for the oxidation of phenylalanine) can reduce blood levels of this amino acid in certain patients. There is now a tablet preparation of the compound sapropterin dihydrochloride (Kuvan),which is a form of tetrahydrobiopterin. Kuvan is the first drug that can help BH4-responsive PKU patients (defined among clinicians as about 1/2 of the PKU population) lower Phe levels to recommended ranges. Working closely with a dietitian, some PKU patients who respond to Kuvan may also be able to increase the amount of natural protein they can eat.

Oculocutaneous albinism; Ocular albinism; Hermansky-Pudlak syndrome Albinism is a defect of melanin production that results in little or no colour (pigment) in the skin, hair, and eyes. Causes, incidence, and risk factors Albinism occurs when one of several genetic defects makes the body unable to produce or distribute melanin, a natural substance that gives color to your hair, skin, and iris of the eye. The defects may be passed down through families. There are two main types of albinism:

Amberlee Peti 12.5

Type 1 albinism is caused by defects that affect production of the pigment, melanin. Type 2 albinism is due to a defect in the "P" gene. People with this type have slight coloring at birth.

The most severe form of albinism is called oculocutaneous albinism. People with this type of albinism have white or pink hair, skin, and iris color, as well as vision problems. Another type of albism, called ocular albinism type 1 (OA1), affects only the eyes. The person's skin and eye colors are usually in the normal range. However, an eye exam will show that there is no coloring in the back of the eye (retina). Hermansky-Pudlak syndrome (HPS) is a form of albinism caused by a single gene. It can occur with a bleeding disorder, as well as with lung and bowel diseases. Other complex diseases may lead to loss of coloring in only a certain area (localized albinism). These conditions include:

Chediak-Higashi syndrome (lack of coloring all over the skin, but not complete) Tuberous sclerosis(small areas without skin coloring ) Waardenburg syndrome (often a lock of hair that grows on the forehead, or no coloring in one or both irises)

Symptoms A person with albinism will have one of the following symptoms:

Absence of colour in the hair, skin, or iris of the eye Lighter than normal skin and hair Patchy, missing skin color

Many forms of albinism are associated with the following symptoms:

Crossed eyes (strabismus) Light sensitivity (photophobia) Rapid eye movements (nystagmus) Vision problems, or functional blindness

Amberlee Peti 12.5

Signs and tests Genetic testing offers the most accurate way to diagnose albinism. Your doctor may also diagnose the condition based on the appearance of your skin, hair, and eyes. An ophthalmologist should perform a electroretinogram test, which can reveal vision problems related to albinism. A visual evoked potentials test can be very useful when the diagnosis is uncertain. Treatment The goal of treatment is to relieve symptoms. Treatment depends on the severity of the disorder. Treatment involves protecting the skin and eyes from the sun:

Reduce sunburn risk by avoiding the sun, using sunscreen, and covering up completely with clothing when exposed to the sun. Sunscreen should have a high sun protection factor (SPF). Sunglasses (UV protected) may relieve light sensitivity.

Glasses are often prescribed to correct vision problems and eye position. Eye muscle surgery is sometimes recommended to correct abnormal eye movements (nystagmus). Expectations (prognosis) Albinism does not usually affect lifespan. People with albinism may be limited in their activities because they can't tolerate the sun. Complications

Decreased vision, blindness Skin cancer

Amberlee Peti 12.5

Intro- PKU is

The incidence of PKU is about 1 in 15,000 births, but the incidence varies widely in different human populations. The illness is also more common in Italy and China, as well as in Yemeni populations. PKU, why does it happen? How? What enzymes and biomolecules involved? Types. Inheritance. Diagnosis- technologies. Treatment-Symptoms.
BT1- Why? What? How? Explanation. (What is- absent enzymes) How it affects the body (metabolic pathways) Compared to Albanism- how different? BT2- Types? Inheritance? Types- Maternal and classical (most common). Differences- similarities. Inheiritance- autosomeal recessive (explain). Chances of inheiriting PKU. BT3- Diagnosis: technology. Screening and presentation Diagnosis (Guthrie and TMS) Interpretation of results. BT4- Treatment: Symptoms. Syptoms- e.g. effects- mental retardation, etc. Treatment- diet change, new pills etc.

Amberlee Peti 12.5