Newborn screening for disease is a highly effective public health effort to prevent the consequences of certain diseases in affected newborns. Through testing of blood samples from and administration of hearing tests to newborn infants, targeted diseases are detected very early, often before manifestations of diseases are evident, enabling rapid initiation of treatment of these diseases. This entry summarizes the mechanism of screening, the diseases screened, and the treatment of some of these diseases and highlights the potential of newborn screening for identification and control of other health problems.
Newborn screening comprises a system through which a laboratory, public or private, processes a newborn blood specimen to detect the possible presence of a disease in the infant. The newborn screen blood sample is usually obtained by a health care provider, typically a hospital nurse. The blood sample is placed on a special newborn screening card, the blood is dried, and the card is then transported to the testing laboratory. If the test is normal, the results are sent to the infant’s health care provider and the testing is complete; if the test is abnormal, newborn screening programs follow-up measures ensure that the infant with a positive result enters into treatment for the disease. These steps include notification of the infant’s physician and family of the positive screening result; obtaining a specimen for a second screening test; and, if the second screen is positive, a visit to a clinical specialist for diagnostic testing (the laboratory screening test typically detects an elevation in a substance that can occasionally be temporary and not indicative of actual disease). Finally, if the diagnostic test indicates the presence of a disease, the infant undergoes the therapeutic treatment recommended by existing clinical standards for the specific disease typically by a specialist trained to care for the specific disorder.
All 50 states and the territories perform screening tests of newborn blood specimens to detect diseases for which a treatment prevents the medical complications of untreated disease. With improvements in testing technology, most newborn screening programs are now expanding the number of disorders for which screening is done. This entry discusses the development of newborn screening, the current expansion of the programs, and the potential for future newborn screening.
Following the rediscovery of Mendel’s genetic principles at the beginning of the 20th century, medical practitioners began to recognize that many human diseases are genetic. Throughout the early part of the century, an understanding of the principles of genetics advanced. Subsequent advances included the identification of deoxyribonucleic acid (DNA) as the genetic material; the delineation of the molecular structure of DNA by Watson and Crick in 1953; and, at the end of the century, completion of the draft sequence of the human genome.
Hand in hand with these advances in genetics were advances in biochemistry. It became clear that while DNA contained the information for life, biochemical pathways and molecules produced from genetic material were the engine of this information. If there is an alteration in genetic information, this typically results in a biochemical disturbance.
In 1902, Sir Archibald Garrod noticed that patients with a disease he called alkaptonuria excreted excessive amounts of alkapton (a urinary chemical that turned the urine to a dark color that was later identified as homogentisic acid) into the urine. Based on the pattern of inheritance Garrod recognized as Mendelian (in this case, recessive), he correctly concluded that this disorder represented a genetic alteration in metabolism. The term inborn errors of metabolism eventually was coined to describe collectively the diseases of patients with genetic defects in biochemical pathways.
Enzymes perform most of the biochemical reactions in cells. They are proteins whose function is to perform a chemical reaction in which one chemical substance is converted into another. The original chemical is called a substrate, and the end chemical is the product. Research over the century has identified thousands of chemical reactions, and these reactions are mediated by thousands of enzymes. If an enzyme does not function, then the reaction does not occur and substrates for the reaction accumulate and products become deficient. As all enzymes are the products of genes, the presence of defective enzymes usually means an alteration in the genetic information present in the patient.
Following Garrod’s initial description, additional inborn errors were identified based on analyses of patient samples. Typically, the substrate for a defective enzymatic reaction accumulates in tissues and blood and is excreted into urine and/or stool where the elevations can be detected by testing. Phenylketonuria (PKU) was recognized as an inborn error in 1934 and determined to be due to elevations of the amino acid phenylalanine due to defective function of the enzyme phenylalanine hydroxylase. Analysis of institutionalized, mentally retarded patients revealed that many of them had PKU. In the 1950s, Dr. Horst Bickel and associates showed that blood levels of phenylalanine could be reduced in PKU patients by a diet low in protein (and, thus, phenylalanine). With reduction of blood phenylalanine levels, many medical symptoms improved. These observations set the stage for newborn screening.
In the early 1960s, motivated in part by a family history of mental retardation, in a son, and phenylketonuria, in a niece, Dr. Robert Guthrie described a method for the detection of elevated blood phenylalanine in blood samples obtained from newborns. He deduced that placement of affected infants on infant formula low in protein would reduce their blood levels of phenylalanine and prevent development of mental retardation. The problem was to identify infants affected with PKU before the onset of symptoms. Guthrie approached public health officials, and policies to screen all newborn infants for PKU were implemented. This effort rapidly spread throughout the United States, and soon all states were screening infants for PKU. Dr. Guthrie’s hypothesis regarding early treatment of PKU by a phenylalanine (protein) restricted diet was correct and highly successful in preventing the devastating complications of untreated disease.
Building on the PKU experience, it was soon recognized that other inborn errors could be detected by assays of accumulated compounds or of enzymes in newborn blood and that many of these additional diseases had effective treatments. From the 1960s to the present, the number of disorders identified through newborn screening programs has slowly increased.
Typically, a newborn screen is obtained from an infant at approximately 24 to 48 hr of age. The heel of the infant is warmed, and a lancet is used to puncture the skin and obtain capillary blood. The drops of blood are placed onto a special filter paper card, and the blood spot is dried. Demographic information is recorded on the card, and it is sent to the screening laboratory.
Once at the laboratory, small circular punches of the dried blood are obtained and processed for analysis. The sample may be tested for chemicals that accumulate due to an enzymatic defect, the activity of a specific enzyme can be assayed, or a protein can be analyzed by biochemical means.
Full testing of the sample usually takes about 2 to 3 days. The results are then compared with laboratorygenerated normal values and the result reported to the infant’s physician. Typically, the result of the newborn screen is complete when the infant is 7 to 10 days of age. This rapid analysis is necessary as some of the disorders for which screening is done can cause critical illness in the first 2 weeks of life. If there is an abnormality, the physician may need to repeat the newborn screen or move to more definitive testing.
Within the past decade, the application of tandem mass spectrometry to newborn screening has enabled significant expansion of the number of disorders that can be detected. This has led organizations such as the American College of Medical Genetics and the March of Dimes to propose a panel of disorders in an attempt to expand and unify newborn screening programs in all states. The recommended panel includes 29 disorders, including congenital hearing loss. These 29 disorders are thought to represent disorders for which a favorable treatment exists. They can be broadly grouped into amino acid disorders, organic acid disorders, fatty acid oxidation defects, hormonal disorders, hemoglobinopathies, vitamin disorders, carbohydrate disorders, pulmonary disorders, and congenital hearing loss. Tandem mass spectrometry does enable testing for other disorders for which effective treatments do not yet exist and leaves the decision for testing of these additional disorders to individual states.
These disorders include some of the first to be part of routine newborn screening programs. PKU is due to a functional defect in the enzyme phenylalanine hydroxylase. As a result, phenylalanine, which derives from dietary protein, accumulates to high levels and, with time, can cause neurologic damage and ultimately mental retardation. Treatment with a low-protein/phenylalanine diet prevents development of these symptoms.
Maple syrup urine disease is due to a functional defect in the enzyme branched chain α-ketoacid dehydrogenase. Accumulation of the branched chain amino acids leucine, isoleucine, and valine and their respective ketoacids is rapidly damaging to the nervous system. Rapid treatment with a low-protein diet reduces these levels and prevents neurologic damage.
Homocystinuria is due to defective function of the enzyme cystathionine-b-synthase. Elevation of methionine and homocysteine occur and, with time, can damage the eye and blood vessels. A low-protein/methionine diet reduces blood levels and the risk of these complications.
Tyrosinemia Type I is due to dysfunction of the enzyme fumarylacetoacetic acid hydrolase. Damage to the liver occurs within 4 to 6 months and can be prevented with medications and a low-tyrosine diet.
Citrullinemia and argininosuccinic acidemia are urea cycle disorders due to defective function of argininosuccinic acid synthase and lyase, respectively. Severe elevations in blood levels of ammonia result and can damage the nervous system. Institution of a low-protein diet helps lower blood ammonia levels and prevent damage.
Organic acid disorders comprise the group providing the largest increase in the number of diseases included in expanded newborn screening programs. Included in the recommended 29 disorders are the following: isovaleric acidemia, glutaric acidemia Type I, 3-hydroxy-3-methylglutaric acidemia, multiple carboxylase deficiency, methymalonic acidemia due to mutase deficiency, cblA and cblB deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, propionic acidemia, and b-ketothiolase deficiency. As a group, they typically present with severe acidosis and neurologic dysfunction. Treatment is effected through institution of a low-protein diet and disease-specific medications.
The fatty acid oxidation defects are due to defective functioning of enzymes involved in the breakdown of stored fat used for energy production. Typically, they cause symptoms during times of insufficient food intake, but some also cause liver or heart damage without fasting. There are many enzymes in these metabolic processes, including medium chain acyl-CoA dehydrogenase, very long chain acyl-CoA dehydrogenase, long chain 3-hydroxy acyl-CoA dehydrogenase, trifunctional protein, and others. Treatment varies with the individual disorder but in general includes avoidance of fasting and limitation of fat intake.
Congenital hypothyroidism is one of the most common disorders detected by newborn screening and was the second disorder (following PKU) to be included on a routine basis in newborn screening programs. Insufficient thyroid hormone production by the thyroid gland, whether due to failure of formation of the gland or due to an enzyme defect in the synthesis of hormone, results in mental retardation and poor growth. Treatment with replacement of thyroid hormone is effective in preventing these symptoms.
Congenital adrenal hyperplasia, due to adrenal 21-hydroxylase deficiency, can cause loss of body salts and masculinization of female genitalia. The loss of body salt can be life threatening. Treatment by hormone replacement can reverse the loss of body salt. Treatment of masculinization of the female genitalia may require surgery.
Hemoglobin is the oxygen-transporting protein present in red blood cells. Genetic alterations in the structure of hemoglobin may alter its function. One of the most common of these defects, that as a group are called hemoglobinopathies, is sickle-cell anemia. This disorder is common in populations of individuals of African American ancestry and causes anemia and a predisposition to bacterial infection that can be prevented with antibiotics. The newborn screen will also detect other clinically significant hemoglobinopathies such as thalassemia and hemoglobin E.
Biotinidase is an enzyme involved in preserving the body’s levels of the important vitamin biotin. When biotinidase function is defective, the body gradually becomes deficient in biotin, and this deficiency disrupts function of biotin-requiring enzymes. The symptoms include skin rash, hair loss, seizures, and neurologic damage. Supplementation with biotin prevents these symptoms.
Classic galactosemia is due to a defect in the function of the enzyme galactose-1-phosphate uridyltransferase. Galactose is a sugar found in a variety of foods, especially in dairy foods containing the disaccharide lactose. Defective functioning of galactose-1-phosphate uridyltransferase causes accumulation of galactose, which can damage the liver and the eyes. Restriction of dietary lactose reduces blood levels and prevents this damage.
Cystic fibrosis is one of the most common genetic diseases in populations of European ancestry. It is due to a defective function of the cystic fibrosis membrane transconductance regulator. Abnormal movement of water and salts within internal body ducts results in abnormally thick mucous. This thick mucous plugs the ducts of the respiratory, reproduction, and gastrointestinal tracts. This causes damage to the pancreas and the lungs. Identification of affected infants allows early treatment for nutritional and growth problems.
Congenital hearing loss is very common, and identification of infants enables interventions to improve speech development. There are many genetic and nongenetic causes of hearing loss in the newborn. Early treatment with speech therapy helps hearing impaired children improve communication skills.
The 29 disorders were recommended for screening because each has some therapeutic intervention that helps prevent development of medical complications. There are, however, many other disorders that could be detected in the newborn screen sample. It is highly likely that testing will be expanded beyond 29 disorders in the future.
The newborn blood sample can contain antibodies that indicate exposure to infectious diseases such as toxoplasmosis, cytomegalovirus, and human immunodeficiency virus. While not genetic diseases, these infectious diseases have important public health considerations that make early identification important. The blood spot may contain substances such as methamphetamine, heroin, and cocaine that would indicate the use of these substances by the mother shortly before delivery. Importantly, the blood sample also contains DNA, the genetic material of the human body. Tests for genetic diseases by analysis of DNA continue to expand at an exponential pace. Potential diseases for testing include certain cancers, Huntington disease, fragile X syndrome, and many other inherited diseases.
Such testing does, however, have ethical and legal risks. Because of public health and legal considerations beyond the medical effects on the infant, such testing would likely require parental informed consent. Additionally, psychological harm may result from knowing in childhood that one is going to develop an untreatable disease in the future, and identification of individuals with a genetic disease may result in discrimination in obtaining health insurance. These are important issues that will need to be resolved by future debate and policy but highlight the testing potential offered by the newborn screen.
Genetic Counseling; Genetic Disorders; Mutation; Screening
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