Phenylketonuria Health Dictionary

A protein that acts as a catalyst for the body’s metabolic processes. The body contains thousands of enzymes, with each cell producing several varieties. The ?rst enzyme was obtained in a reasonably pure state in 1926. Since then, several hundred enzymes have been obtained in pure crystalline form. They are present in the digestive ?uids and in many of the tissues, and are capable of producing in small amounts the transformation on a large scale of various compounds. Examples of enzymes are found in the PTYALIN of saliva and DIASTASE of pancreatic juice which split up starch into sugar; the PEPSIN of the gastric juice and the trypsin of pancreatic juice which break proteins into simpler molecules and eventually into the constituent amino acids; and the thrombin of the blood which causes coagulation.

The diagnosis of certain disorders can be helped by measuring the concentrations of various enzymes in the blood. After a heart attack (myocardial infarction – see HEART, DISEASES OF), raised levels of heart enzymes occur as a result of damage to the cells of the heart muscle. Some inherited diseases such as GALACTOSAEMIA and PHENYLKETONURIA are the result of de?ciencies of certain enzymes.

Enzymes can be a useful part of treatment for some disorders. STREPTOKINASE, for example, is used to treat THROMBOSIS; wound-dressings containing papain from the pawpaw fruit – this contains protein-digesting enzymes – assist in the healing process; and pancreatic enzymes can be of value to patients with malabsorption caused by disorders of the PANCREAS.... enzyme

Paediatrics is the branch of medicine which deals with diseases of children, but many paediatricians have a wider role, being employed largely outside acute hospitals and dealing with child health in general.

History Child health services were originally designed, before the NHS came into being, to ?nd or prevent physical illness by regular inspections. In the UK these were carried out by clinical medical o?cers (CMOs) working in infant welfare clinics (later, child health clinics) set up to ?ll the gap between general practice and hospital care. The services expanded greatly from the mid 1970s; ‘inspections’ have evolved into a regular screening and surveillance system by general practitioners and health visitors, while CMOs have mostly been replaced by consultant paediatricians in community child health (CPCCH).

Screening Screening begins at birth, when every baby is examined for congenital conditions such as dislocated hips, heart malformations, cataract and undescended testicles. Blood is taken to ?nd those babies with potentially brain-damaging conditions such as HYPOTHYROIDISM and PHENYLKETONURIA. Some NHS trusts screen for the life-threatening disease CYSTIC FIBROSIS, although in future it is more likely that ?nding this disease will be part of prenatal screening, along with DOWN’S (DOWN) SYNDROME and SPINA BIFIDA. A programme to detect hearing impairment in newborn babies has been piloted from 2001 in selected districts to ?nd out whether it would be a useful addition to the national screening programme. Children from ethnic groups at risk of inherited abnormalities of HAEMOGLOBIN (sickle cell disease; thalassaemia – see under ANAEMIA) have blood tested at some time between birth and six months of age.

Illness prevention At two months, GPs screen babies again for these abnormalities and start the process of primary IMMUNISATION. The routine immunisation programme has been dramatically successful in preventing illness, handicap and deaths: as such it is the cornerstone of the public health aspect of child health, with more potential vaccines being made available every year. Currently, infants are immunised against pertussis (see WHOOPING COUGH), DIPHTHERIA, TETANUS, POLIOMYELITIS, haemophilus (a cause of MENINGITIS, SEPTICAEMIA, ARTHRITIS and epiglottitis) and meningococcus C (SEPTICAEMIA and meningitis – see NEISSERIACEAE) at two, three and four months. Selected children from high-risk groups are o?ered BCG VACCINE against tuberculosis and hepatitis vaccine. At about 13 months all are o?ered MMR VACCINE (measles, mumps and rubella) and there are pre-school entry ‘boosters’ of diphtheria, tetanus, polio, meningococcus C and MMR. Pneumococcal vaccine is available for particular cases but is not yet part of the routine schedule.

Health promotion and education Throughout the UK, parents are given their child’s personal health record to keep with them. It contains advice on health promotion, including immunisation, developmental milestones (when did he or she ?rst smile, sit up, walk and so on), and graphs – called centile charts – on which to record height, weight and head circumference. There is space for midwives, doctors, practice nurses, health visitors and parents to make notes about the child.

Throughout at least the ?rst year of life, both parents and health-care providers set great store by regular weighing, designed to pick up children who are ‘failing to thrive’. Measuring length is not quite so easy, but height measurements are recommended from about two or three years of age in order to detect children with disorders such as growth-hormone de?ciency, malabsorption (e.g. COELIAC DISEASE) and psychosocial dwar?sm (see below).

All babies have their head circumference measured at birth, and again at the eight-week check. A too rapidly growing head implies that the infant might have HYDROCEPHALUS – excess ?uid in the hollow spaces within the brain. A too slowly growing head may mean failure of brain growth, which may go hand in hand with physically or intellectually delayed development.

At about eight months, babies receive a surveillance examination, usually by a health visitor. Parents are asked if they have any concerns about their child’s hearing, vision or physical ability. The examiner conducts a screening test for hearing impairment – the so-called distraction test; he or she stands behind the infant, who is on the mother’s lap, and activates a standardised sound at a set distance from each ear, noting whether or not the child turns his or her head or eyes towards the sound. If the child shows no reaction, the test is repeated a few weeks later; if still negative then referral is made to an audiologist for more formal testing.

The doctor or health visitor will also go through the child’s developmental progress (see above) noting any signi?cant deviation from normal which merits more detailed examination. Doctors are also recommended to examine infants developmentally at some time between 18 and 24 months. At this time they will be looking particularly for late walking or failure to develop appropriate language skills.... child health

See PHENYLKETONURIA.... pku

A common name for the intestine.

Guthrie test A blood test performed routinely on a heel-prick blood sample taken from babies between the 8th and 14th day after birth to check for the inherited disorder phenylketonuria.... gut

n. an artificial sweetener (E951) 200 times sweeter than sugar. Aspartame is metabolized by the body into its constituents – aspartic acid, phenylalanine, and methanol – and is therefore not suitable for people with *phenylketonuria. It can be used in diabetic foods.... aspartame

(heel-prick blood test) a blood test performed on all newborn babies at the end of the first week of life. The blood is obtained by pricking the heel of the baby. The test can detect several *inborn errors of metabolism (including *phenylketonuria) and *hypothyroidism; it can also be used for detecting *cystic fibrosis, although this is not routinely offered. [R. Guthrie (1916–95), US paediatrician]... guthrie test

any one of a group of inherited conditions in which there is a disturbance in either the structure, synthesis, function, or transport of protein molecules. There are over 1500 inborn errors of metabolism; examples are *phenylketonuria, *homocystinuria, and *hypogammaglobulinaemia.... inborn error of metabolism

*screening tests carried out on newborn babies to detect diseases that appear in the neonatal period, such as phenylketonuria (see Guthrie test). If these diseases are detected early enough, treatment may be instigated before any irreversible damage occurs to the baby.... neonatal screening

A collection of disorders in which some part of the body’s internal chemistry (see METABOLISM; CATABOLISM) is disrupted. Some of these disorders arise from inherited de?ciencies in which a speci?c ENZYME is absent or abnormal, or does not function properly. Other metabolic disorders occur because of malfunctions in the endocrine system (see ENDOCRINE GLANDS). There may be over- or underproduction of a hormone involved in the control of metabolic activities: a prime example is DIABETES MELLITUS – a disorder of sugar metabolism; others include CUSHING’S SYNDROME; hypothyroidism and hyperthyroidism (see THYROID GLAND, DISEASES OF); and insulinoma (an insulin-producing tumour of the pancreas). The bones can be affected by metabolic disorders such as osteoporosis, osteomalacia (rickets) and Paget’s disease (see under BONE, DISORDERS OF). PORPHYRIAS, HYPERLIPIDAEMIA, HYPERCALCAEMIA and gout are other examples of disordered metabolism.

There are also more than 200 identi?ed disorders described as inborn errors of metabolism. Some cause few problems; others are serious threats to an individual’s life. Individual disorders are, fortunately, rare – probably one child in 10,000 or 100,000; overall these inborn errors affect around one child in 1,000. Examples include GALACTOSAEMIA, PHENYLKETONURIA, porphyrias, TAY SACHS DISEASE and varieties of mucopolysaccharidosis, HOMOCYSTINURIA and hereditary fructose (a type of sugar) intolerance.... metabolic disorders

Degeneration or death of nerve cells and tracts within the brain that may be localized to a particular area of the brain or diffuse. Diffuse damage most commonly results from prolonged cerebral hypoxia (which may occur in a baby during a difficult birth), cardiac arrest, respiratory arrest, or causes such as poisoning or status epilepticus (prolonged convulsions). The damage may also occur gradually due to environmental pollutants such as lead or mercury compounds (see Minamata disease) or if nerve-cell poisons build up in the brain, as in untreated phenylketonuria. Other possible causes include brain infections such as encephalitis.

Localized brain damage may occur as a result of a head injury, stroke, brain tumour, or brain abscess. At birth, a raised blood level of bilirubin (in haemolytic disease of the newborn) causes local damage to the basal ganglia deep within the brain. This leads to a condition called kernicterus. Brain damage that occurs before, during, or after birth may result in cerebral palsy.

Damage to the brain may result in disabilities such as learning difficulties or disturbances of movement or speech.

Nerve cells and tracts in the brain and spinal cord cannot repair themselves once they have been damaged, but some return of function may be possible.... brain damage

Inherited defects of body chemistry. Inborn errors of metabolism are caused by single gene defects, which lead to abnormal functioning of an enzyme.

Some of these gene defects are harmless, but others are severe enough to result in death or physical or mental handicap. Examples include Tay–Sachs disease, phenylketonuria, Hurler’s syndrome, and Lesch–Nyhan syndrome. Collectively, inborn errors of metabolism affect around 1 child in 5,000.

Symptoms are usually present at or soon after birth. They may include unexplained illness or failure to thrive, developmental delay, floppiness, persistent vomiting, or seizures.

Routine tests are performed on newborn babies for some genetic disorders, such as phenylketonuria.

Treatment is not needed for some inborn errors of metabolism. For others, avoidance of a specific environmental factor may be sufficient. In some cases, the missing enzyme or the protein that it produces can be manufactured using genetic engineering techniques, or a vitamin supplement can help compensate for the defective enzyme. If the enzyme is made in blood cells, a bone marrow transplant may provide a cure.

People with a child or a close relative who is affected may benefit from genetic counselling before planning a pregnancy.... metabolism, inborn errors of

n. an *essential amino acid that is readily converted to tyrosine. Blockade of this metabolic pathway gives rise to *phenylketonuria, which is associated with abnormally large amounts of phenylalanine and phenylpyruvic acid in the blood and retarded mental development.... phenylalanine

These are caused when there are mutations or other abnormalities which disrupt the code of a gene or set of GENES. These are divided into autosomal (one of the 44 CHROMOSOMES which are not sex-linked), dominant, autosomal recessive, sex-linked and polygenic disorders.

Dominant genes A dominant characteristic is an e?ect which is produced whenever a gene or gene defect is present. If a disease is due to a dominant gene, those affected are heterozygous – that is, they only carry a fault in the gene on one of the pair of chromosomes concerned. A?ected people married to normal individuals transmit the gene directly to one-half of the children, although this is a random event just like tossing a coin. HUNTINGTON’S CHOREA is due to the inheritance of a dominant gene, as is neuro?bromatosis (see VON RECKLINGHAUSEN’S DISEASE) and familial adenomatous POLYPOSIS of the COLON. ACHONDROPLASIA is an example of a disorder in which there is a high frequency of a new dominant mutation, for the majority of affected people have normal parents and siblings. However, the chances of the children of a parent with the condition being affected are one in two, as with any other dominant characteristic. Other diseases inherited as dominant characteristics include spherocytosis, haemorrhagic telangiectasia and adult polycystic kidney disease.

Recessive genes If a disease is due to a recessive gene, those affected must have the faulty gene on both copies of the chromosome pair (i.e. be homozygous). The possession of a single recessive gene does not result in overt disease, and the bearer usually carries this potentially unfavourable gene without knowing it. If that person marries another carrier of the same recessive gene, there is a one-in-four chance that their children will receive the gene in a double dose, and so have the disease. If an individual sufferer from a recessive disease marries an apparently normal person who is a heterozygous carrier of the same gene, one-half of the children will be affected and the other half will be carriers of the disease. The commonest of such recessive conditions in Britain is CYSTIC FIBROSIS, which affects about one child in 2,000. Approximately 5 per cent of the population carry a faulty copy of the gene. Most of the inborn errors of metabolism, such as PHENYLKETONURIA, GALACTOSAEMIA and congenital adrenal hyperplasia (see ADRENOGENITAL SYNDROME), are due to recessive genes.

There are characteristics which may be incompletely recessive – that is, neither completely dominant nor completely recessive – and the heterozygotus person, who bears the gene in a single dose, may have a slight defect whilst the homozygotus, with a double dose of the gene, has a severe illness. The sickle-cell trait is a result of the sickle-cell gene in single dose, and sickle-cell ANAEMIA is the consequence of a double dose.

Sex-linked genes If a condition is sex-linked, affected males are homozygous for the mutated gene as they carry it on their single X chromosome. The X chromosome carries many genes, while the Y chromosome bears few genes, if any, other than those determining masculinity. The genes on the X chromosome of the male are thus not matched by corresponding genes on the Y chromosome, so that there is no chance of the Y chromosome neutralising any recessive trait on the X chromosome. A recessive gene can therefore produce disease, since it will not be suppressed by the normal gene of the homologous chromosome. The same recessive gene on the X chromosome of the female will be suppressed by the normal gene on the other X chromosome. Such sex-linked conditions include HAEMOPHILIA, CHRISTMAS DISEASE, DUCHENNE MUSCULAR

DYSTROPHY (see also MUSCLES, DISORDERS OF – Myopathy) and nephrogenic DIABETES INSIPIDUS.

If the mother of an affected child has another male relative affected, she is a heterozygote carrier; half her sons will have the disease and half her daughters will be carriers. The sister of a haemophiliac thus has a 50 per cent chance of being a carrier. An affected male cannot transmit the gene to his son because the X chromosome of the son must come from the mother; all his daughters, however, will be carriers as the X chromosome for the father must be transmitted to all his daughters. Hence sex-linked recessive characteristics cannot be passed from father to son. Sporadic cases may be the result of a new mutation, in which case the mother is not the carrier and is not likely to have further affected children. It is probable that one-third of haemophiliacs arise as a result of fresh mutations, and these patients will be the ?rst in the families to be affected. Sometimes the carrier of a sex-linked recessive gene can be identi?ed. The sex-linked variety of retinitis pigmentosa (see EYE, DISORDERS OF) can often be detected by ophthalmoscopic examination.

A few rare disorders are due to dominant genes carried on the X chromosome. An example of such a condition is familial hypophosphataemia with vitamin-D-resistant RICKETS.

Polygenic inheritance In many inherited conditions, the disease is due to the combined action of several genes; the genetic element is then called multi-factorial or polygenic. In this situation there would be an increased incidence of the disease in the families concerned, but it will not follow the Mendelian (see MENDELISM; GENETIC CODE) ratio. The greater the number of independent genes involved in determining a certain disease, the more complicated will be the pattern of inheritance. Furthermore, many inherited disorders are the result of a combination of genetic and environmental in?uences. DIABETES MELLITUS is the most familiar of such multi-factorial inheritance. The predisposition to develop diabetes is an inherited characteristic, although the gene is not always able to express itself: this is called incomplete penetrance. Whether or not the individual with a genetic predisposition towards the disease actually develops diabetes will also depend on environmental factors. Diabetes is more common in the relatives of diabetic patients, and even more so amongst identical twins. Non-genetic factors which are important in precipitating overt disease are obesity, excessive intake of carbohydrate foods, and pregnancy.

SCHIZOPHRENIA is another example of the combined effects of genetic and environmental in?uences in precipitating disease. The risk of schizophrenia in a child, one of whose parents has the disease, is one in ten, but this ?gure is modi?ed by the early environment of the child.... genetic disorders

Coloration of the skin, hair, and iris of the eyes by melanin. The more melanin present, the darker the coloration. Blood pigments can also colour skin (such as in a bruise).

There are many abnormalities of pigmentation.

Patches of pale skin occur in psoriasis, pityriasis alba, pityriasis versicolor, and vitiligo.

Albinism is caused by generalized melanin deficiency.

Phenylketonuria results in a reduced melanin level, making sufferers pale-skinned and fair-haired.

Areas of dark skin may be caused by disorders such as eczema or psoriasis, pityriasis versicolor, chloasma, or by some perfumes and cosmetics containing chemicals that cause photosensitivity.

Permanent areas of deep pigmentation, such as freckles and moles (see naevus), are usually due to an abnormality of melanocytes.

Acanthosis nigricans is characterized by dark patches of velvet-like, thickened skin.

Blood pigments may lead to abnormal colouring.

Excess of the bile pigment bilirubin in jaundice turns the skin yellow, and haemochromatosis turns the skin bronze.... pigmentation