Newborn Screening for Genetic and Metabolic Disorders

35 Congenital Conditions Recommended for Routine Screening

Newborn Screening Test

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With many congenital disorders, the symptoms won't become apparent until days or weeks after the child is born. By that time, damage may have already been done to the heart, lungs, kidneys, nervous system, and other vital organs. This is why the routine screening of genetic and metabolic disorders in newborns is so essential. By detecting anomalies early, doctors may be able to help slow or prevent the progression of certain diseases.

Currently, in the United States, there are 35 genetic and metabolic disorders routinely screened in newborns as well as 26 secondary disorders for which screening is recommended.

History

The concept of newborn screening began in the 1960s with the development of a genetic screening test for phenylketonuria, a metabolic birth defect. The innovative method and collecting and transporting blood samples on filter paper made wide-scale screening not only viable but cost-effective.

Since then, many more blood-based screening tests have been developed, including newer tandem mass spectrometry (MS/MS) technologies that can screen for multiple disorders using only a few drops of blood. In addition to blood-based tests, hearing is routinely screened in newborns to detect hearing loss.

Today, over 98% of the four million newborns born annually in the United States are tested for more than 30 treatable genetic, metabolic, endocrine, and infectious diseases within the first week of life.

Newborn Screening in the United States

The Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) issues regular advisements known as the Recommended Universal Screening Panel (RUSP) which lists the core conditions for which newborn screening is highly recommended and secondary conditions for which screening is optional.

While all 50 states and the District of Columbia offer newborn screening, there is no federal law governing such screenings. Because of this, states can opt to change the panel of disorders listed in the RUSP and/or shift the responsibility for testing from the state to the individual doctor or facility. This can lead to a significant lack of equity in some states.

As of 2017, 49 states and the District of Columbia screen for 30 or more of the core conditions recommended by the ACHDNC. Only North Carolina screens for less (29). Other states like California screen for more than the core 34 and, by doing so, significantly reduce their annual cost of health care.

The funding of screening programs continues to challenge many state legislatures. To overcome this, a bill called the Newborn Screening Saves Lives Reauthorization Act was introduced in the U.S. House of Representatives in May 2019 to improve and expand current newborn screening initiatives throughout the United States.

Core and Secondary Screening

As of July 2018, there are 34 core conditions that the ACHDNC recommends be included in routine newborn screenings:

  1. Propionic acidemia
  2. Methylmalonic acidemia (methylmalonyl-CoA mutase)
  3. Methylmalonic acidemia (cobalamin disorders)
  4. Isovaleric acidemia
  5. 3-methylcrotonyl-CoA carboxylase deficiency
  6. 3-hydroxy-3-methylglutaric aciduria
  7. Holocarboxylase synthase deficiency
  8. Beta-ketothiolase deficiency
  9. Glutaric acidemia type I
  10. Carnitine uptake/transport defect
  11.  Medium-chain acyl-CoA dehydrogenase deficiency
  12.  Very long-chain acyl-CoA dehydrogenase deficiency
  13.  Long-chain L-3 hydroxyacyl-CoA dehydrogenase deficiency
  14. Trifunctional protein deficiency
  15. Argininosuccinic aciduria
  16. Citrullinemia, type I
  17. Maple syrup urine disease
  18. Homocystinuria
  19. Phenylketonuria
  20. Tyrosinemia, type I
  21. Primary congenital hypothyroidism
  22. Congenital adrenal hyperplasia
  23. Sickle cell anemia (SS disease)
  24. Sickle beta-thalassemia
  25. Sickle cell disease (SC disease)
  26. Biotinidase deficiency
  27. Critical congenital heart disease
  28. Cystic fibrosis
  29. Galactosemia
  30. Glycogen storage disease type II
  31. Congenital hearing loss
  32. Severe combined Immunodeficiencies
  33. Mucopolysaccharidosis Type 1
  34. X-linked adrenoleukodystrophy
  35. Spinal muscular atrophy due to homozygous deletion

In addition, there are 24 secondary conditions that the ACHDNC recommends be considered as part of routine screening:

  1. Methylmalonic acidemia with homocystinuria
  2. Malonic acidemia
  3. Isobutyrylglycinuria
  4. 2-Methylbutyrylglycinuria
  5. 3-Methylglutaconic aciduria
  6. 2-Methyl-3-hydroxybutyric aciduria
  7. Short-chain acyl-CoA dehydrogenase deficiency
  8. Medium/short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency
  9. Glutaric acidemia type II
  10. Medium-chain ketoacyl-CoA thiolase deficiency
  11. 2,4 Dienoyl-CoA reductase deficiency
  12. Carnitine palmitoyltransferase type I deficiency
  13. Carnitine palmitoyltransferase type II deficiency
  14. Carnitine acylcarnitine translocase deficiency
  15. Argininemia
  16. Citrullinemia, type II
  17. Hypermethioninemia
  18. Benign hyperphenylalaninemia
  19. Biopterin defect in cofactor biosynthesis
  20. Biopterin defect in cofactor regeneration
  21. Tyrosinemia type II
  22. Tyrosinemia type III
  23. Various other hemoglobinopathies
  24. Galactoepimerase deficiency
  25. Galactokinase deficiency
  26. T-cell related lymphocyte deficiencies

Newborn Screening Around the World

Screening for disorders is part of newborn healthcare in all developed countries. Most countries screen for phenylketonuria, congenital hypothyroidism, and cystic fibrosis. Many also screen for congenital adrenal hyperplasia, galactosemia, and sickle cell disease, and other more common disorders.

However, many developing countries are falling behind in their screening efforts due to the lack of funding and/or healthcare infrastructure. According to a 2016 report in Clinical Chemistry, countries in Latin America and Asia-Pacific generally screen for only a small handful of core conditions. Even in the private sector, screenings typically involve half of the core conditions commonly tested in the United States.

How Screening Is Done

The process of newborn screening is relatively quick and easy. Between 24 hours to seven days after birth, a few drops of blood are taken from an infant’s heel and placed on a special card. The paper is sent to a specialized laboratory for testing.

The results of the blood tests are sent to the infant's pediatrician within two to seven days. If any of the tests come back positive, further testing will be done to confirm the diagnosis. Parents do not have to request the tests; they should be automatically performed.

In addition to blood-based tests, a hearing test will be performed to check for hearing loss. It is a non-invasive test that only takes around five to 10 minutes to complete.

There are two standard methods of detecting hearing loss in newborns:

  • Otoacoustic emissions (OAE) in which a miniature earphone and microphone can confirm hearing if sounds are reflected back from the ear canal
  • Auditory brain stem response (ABR) in which electrodes placed on the newborn's head can detect the presence or absence of brain’s response to sounds
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