Newborn Screening for Genetic Disorders

Experiments on Plant Hybridization

Todd T. Eckdahl

• Publisher: Momentum Press
• Year: 2018
• Print ISBN: 9781944749699
• eBook ISBN: 9781944749705
• Topic: Biological Sciences
• Subtopic: Genetics in Medicine
• Index: Biological Sciences

This book describes newborn screening as a public health program for the early detection of genetic disorders.

It presents the recommended uniform screening panel (RUSP), a list of genetic disorders recommended by the U.S. government for states to include in newborn screening programs. The author describes the categorization of RUSP genetic disorders, discusses the symptoms and health complications of examples from each category, and explains clinical laboratory tests used for newborn screening.

The book explores the underlying molecular genetic causes of genetic disorders, and how this information is used for genetic testing during newborn screening and diagnosis. It presents the patterns of inheritance of monogenic genetic disorders, and uses hypothetical family scenarios to illustrate them. Treatments and therapies for selected RUSP genetic disorders are described that illustrate the benefits of early diagnosis. The book describes future prospects for the prevention, diagnosis, and treatment of genetic disorders detected by newborn screening, including experimental drug treatments, the possibility of newborn genome sequencing, and gene therapy.

CHAPTER 1

Symptoms and Diagnosis

The recommended uniform screening panel (RUSP) is a list of genetic disorders that the Secretary of the U.S. Department of Health and Human Services (HHS) recommends for use in the establishment of newborn screening programs. Each state and territory is responsible for passing laws that establish its own panel of genetic disorders to be included in a newborn screening program. Variations in panels among states occur because of differences in the prevalence of various genetic disorders, the costs of screening, the amount of public funding for screening, and the availability of treatments for genetic disorders. Many states provide funding for the diagnosis, treatment, and ongoing evaluation of infants who test positive for a genetic disorder. The RUSP is currently composed of 35 genetic disorders referred to as core conditions and 26 secondary conditions that also can be detected during screening for RUSP core conditions. The HHS Secretary regularly updates the RUSP by collaborating with the Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) to consider proposals from researchers, organizations, and parents of children affected by genetic disorders. The following are the criteria for inclusion of a genetic disorder on the RUSP: (1) that there should be a specific and sensitive genetic test available to detect the disorder; (2) that the course of symptoms and health complications should be well understood; (3) that an effective treatment should be available; and (4) that information about whether the occurrence of the disorder would affect future reproductive decisions of the affected family should be available.

RUSP core conditions are organized into categories according to their underlying causes and the body systems affected. Twenty of the disorders are categorized as metabolic disorders, which means that they disrupt metabolism. Metabolism can be subdivided into catabolism, the processes by which enzymes extract energy from food in support of cellular activities throughout the body, and anabolism, the use of chemical building blocks derived from the breakdown of food to synthesize proteins, lipids, carbohydrates, and nucleic acids responsible for the structure and function of cells. Metabolic disorders are subcategorized on the RUSP into those that affect the metabolism of organic acids, fatty acids, and amino acids. Two RUSP core conditions are categorized as endocrine disorders and three as hemoglobin disorders. The remaining 10 RUSP core conditions are categorized as “other disorders” because they affect a variety of body systems and have disparate underlying causes. The RUSP also lists secondary conditions, defined as genetic disorders that can be identified when screening newborns for RUSP core conditions. Although most of the 26 secondary conditions currently on the RUSP are metabolic disorders, hemoglobin disorders and a genetic disease affecting the immune system are also included.

Symptoms of Genetic Disorders Identified by Newborn Screening

Organic acid disorders (OADs) are RUSP metabolic disorders that affect catabolism. OADs occur because of inherited errors in catabolic pathways for the degradation of amino acids, carbohydrates, and lipids. OADs cause organic acidemia, an abnormal accumulation of harmful organic acids in the blood, or organic aciduria, an abnormal accumulation of harmful organic acids in the urine. The term organic acid refers to a wide variety of carbon-containing chemicals that have acidic properties because of chemical groups that include oxygen, sulfur, or phosphorus. In the context of genetic disorders, organic acids are limited to chemicals that have one of two types of chemical groups called carboxylic acid or phenolic acid. Table 1.1 lists the nine OADs currently on the RUSP, along with their estimated rates of occurrence among newborns. Although each OAD is characterized by the accumulation of a different organic acid, they cause similar symptoms and health complications. Most OADs have a severe form that causes symptoms in newborns. Symptoms include lethargy, drowsiness, poor feeding, vomiting, diarrhea, rapid heart rate, and low body temperature. Infants with an OAD often have weak muscle tone, known as hypotonia, and are prone to muscle spasms. Because the early symptoms can transition rapidly to heart problems, seizures, or coma, OADs can constitute a neonatal emergency. Some OAD forms present their first symptoms later in infancy, early childhood, or in teenage years. Although they are associated with the same types of symptoms as severe forms, these late-onset forms of OAD have milder symptoms that often come and go with time and can be triggered by environmental influences such as infectious disease or changes in diet. Both the severe and mild forms of OADs cause an increased risk of heart problems and neurological damage, including brain damage, intellectual disability, and vision problems. Children and adults with OADs are also at greater risk of serious health complications from infectious diseases such as colds and flu because part of the immune response is the release of biomolecules that are metabolized into harmful organic acids.

Table 1.1 RUSP organic acid disorders

Disorder	Live birth prevalence
Isovaleric acidemia (IVA)	1 in 25,000
Glutaric acidemia type I (GA1)	1 in 35,000
3-Methylcrotonyl-CoA carboxylase (3MCC) deficiency	1 in 35,000
Methylmalonic acidemia (MA), vitamin B^12-responsive	1 in 55,000
Methylmalonic acidemia, methylmalonyl-CoA mutase (MUT) deficiency	1 in 75,000
Holocarboxylase synthetase deficiency (HCSD)	1 in 90,000
Propionic acidemia (PROP)	1 in 100,000
Beta-ketothiolase (BKT) deficiency	<1 in 1,000,000
3-Hydroxy-3-methylglutaric aciduria (HMG)	<1 in 1,000,000

A second subtype of metabolic disorders on the RUSP called fatty acid oxidation disorders (FAODs) results from a diminished catabolic capacity to extract energy from fats and the subsequent accumulation of harmful fatty acids. Table 1.2 lists the five FAODs currently on the RUSP and their estimated rates of occurrence among newborns. The onset of symptoms varies among FAODs and ranges from infancy to early childhood. Because deficiencies in enzymes needed to extract energy from fat place an extra burden on gaining energy from blood glucose, FAODs are associated with hypoglycemia, a condition of abnormally low blood sugar that can cause short-term weakness, vomiting, seizures, and confusion. Long-term effects of hypoglycemia include delayed cognitive and physical development, an increased risk of coma, and heart problems such as an enlarged heart and the risk of heart failure. FAODs can also produce metabolic acidosis, an accumulation of organic acids in the blood that causes nausea, vomiting, and breathing problems, or hyperammonemia, an excess of ammonia in the blood that can lead to brain injury and death. FAODs sometimes cause damage to nerves in the hands and feet, deterioration of muscles, and liver problems. Some FAODs, such as long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, cause health problems in pregnant women whose fetuses have LCHAD deficiency. These women can experience hemolysis, which is the breakdown of red blood cells (RBCs), low platelet count, and liver damage. LCHAD deficiency can also cause vision loss in infants.

Table 1.2 RUSP fatty acid oxidation disorders

Disorder	Live birth prevalence
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency	1 in 20,000
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency	1 in 20,000
Trifunctional protein (TPF) deficiency	1 in 20,000
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency	1 in 50,000
Systemic primary carnitine deficiency (SPCD)	1 in 100,000

Metabolic disorders can also take the form of amino acid metabolism disorders, which are caused by the inability to catabolically break down the amino acid building blocks of dietary proteins or the inability to transport amino acids into cells for the anabolic production of proteins. Table 1.3 lists the six amino acid metabolism disorders on the RUSP and estimated rates by which they affect newborns. Characteristic signs of some amino acid metabolism disorders occur because of the abnormal accumulation of harmful biomolecules in body fluids. Maple syrup urine disease (MSUD) is named for the unusual smell it causes in the urine and sweat of affected children. Children with phenylketonuria (PKU) often have a noticeably musty body odor. Some symptoms of amino acid metabolism disorders appear within days of birth and others appear in early childhood. Symptoms among newborns include lethargy, nausea, vomiting, seizures, and coma. Some infants have abdominal pain from liver dysfunction. In early childhood, symptoms can include abnormal curvature of the spine, osteoporosis, anemia, weight loss, vomiting, diarrhea, and hypotonia, as well as an increased risk of stroke and high blood pressure. Sometimes an amino acid metabolism disorder causes dislocation of the lens of the eye, resulting in impaired vision. Children with amino acid metabolism disorders are often at risk of developing intellectual disability and sometimes display hyperactivity, irritability, extreme aggression, and self-injurious behavior. The symptoms of amino acid disorders sometimes persist into adulthood and can be triggered by infectious disease, surgery, or changes in diet.

Table 1.3 RUSP amino acid metabolism disorders

Disorder	Live birth prevalence
Classic pheny...

Table of contents

• Cover
• Half Title Page
• Title Page
• Copyright
• Contents
• Acknowledgments
• Introduction.
• Chapter 1 Symptoms and Diagnosis
• Chapter 2 Causes and Contributing Factors
• Chapter 3 Treatment and Therapy
• Chapter 4 Future Prospects
• Conclusion
• Glossary
• Bibliography
• About the Author
• Index