 |
||||||||||||||||||||||||||||||||||||
 |
||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
Inborn errors of metabolism include a vast array of disorders that are caused by deficiencies of specific enzymes or transport proteins. The goal of newborn screening is the presymptomatic diagnosis of disorders for which early treatment can reduce morbidity and mortality. State mandated newborn screening was initiated in the early 1960s to identify infants affected with phenylketonuria (PKU). Screening programs have gradually expanded to include additional inborn errors, but state mandated programs are not uniform across the United States. Until recently, the Missouri Department of Health has screened for five disorders including phenylketonuria, congenital hypothyroidism, congenital adrenal hyperplasia, galactosemia and hemoglobinopathy. The incidence of these inborn errors of metabolism during the last 5 years is summarized below.
In April 18, 2001, Missouri Bill #279 recommended that the newborn screening program be expanded to test for at least 16 more disorders by January 1, 2002. During the last decade, tandem mass spectrometry has been adapted for supplemental newborn screening because it is amenable to population-wide testing for more than 30 disorders of fatty acid, organic acid and amino acid metabolism. On July 1, 2005, Missouri expanded its newborn screening panel to test for 20 additional inborn errors, which are categorized into Fatty Acid Oxidation, Organic Acid and Amino Acid Disorders. The complete list includes:
The Missouri State Newborn Screening Laboratory published their results for 2008 in which 80,926 Initial Newborn Screens were performed. There were 709 low risk results and 131 moderate and high risk results. The low risk results usually required only a repeat screen because they were only slightly elevated and the infants were not expected to be affected by these disorders. The moderate and high risk results required diagnostic confirmatory testing. Twenty seven of the 131 moderate and high positives were confirmed to be true positives. The positive predictive value (PPV) was 21%, which compares favorably with the national target PPV of 20% or greater. The probability that a Missouri newborn born in 2008 had a disorder detected by tandem mass spectrometry was 1 in 2997. The following table summarizes the number and type of deficiencies detected.
Several of the 104 false positive results had elevated metabolite levels during confirmatory testing that were subsequently shown to be transient. In May 2007, the Missouri State Public Health Laboratory began conducting a pilot program for newborn cystic fibrosis screening utilizing a fluroimmunoassay to measure immunoreactive trypsinogen (IRT). Newborns with cystic fibrosis have persistently elevated IRT levels, whereas unaffected infants may have transiently elevated levels at birth that return to normal after the first week of life. The Missouri State laboratory will request a repeat screen for all infants that have elevated IRT levels on the initial newborn screen. These will be collected at no charge to the parents. If the IRT levels are elevated on the repeat screen, the physician of record will be contacted by a cystic fibrosis center for additional follow up testing. No additional blood spots are required for the expanded screening; the State lab will continue to use the 5-spot collection cards. The laboratories at Saint Luke's Hospital and Saint Luke's Northland Hospital will continue their policy of sending letters to parents and contacting the physician of record when abnormal results are obtained from the State laboratory. The pros and cons of supplemental newborn screening by tandem mass spectrometry are being hotly debated. Pro-active groups, such as Savebabies.org, and parents of infants born with treatable diseases have spearheaded the development of supplemental newborn screening programs. Recent studies have associated 5% of SIDS to metabolic disorders that can be detected by supplemental screening. However, many experts believe that tandem mass spectrometry should not be used in newborn screening until more is known about its sensitivity and specificity. Given the low prevalence of these metabolic disorders in the general population, the number of false positive results will greatly exceed the number of true positives. Sufficient resources need to be available to handle the increased number of abnormal results that will need to be further investigated. In most newborn screening programs, 75% or more of staff time is devoted to follow-up of false positive results. Once an abnormal result is obtained, additional confirmatory testing will need to be performed. Another concern is that there may not be enough pediatric specialists in the United States to evaluate all of the newborns with abnormal results in a timely manner. The issue of informed consent for supplemental screening is complicated, in part because uniformly effective therapies have not been developed for all the conditions that can be detected and because expanded screening may detect previously unrecognized disorders. Reimbursement is also problematic. Supplemental screening costs vary from $25 to $60, but consultation and confirmatory testing are much more expensive. Presently, it is unclear whether private insurance or state and federal programs will cover any of these costs. Second Tier Follow-up Testing for Congenital Adrenal Hyperplasia Newborn screening includes testing for congenital adrenal hyperplasia (CAH), which is an autosomal recessive disorder that affects approximately 1 in 10,000 newborns and results in deficient secretion of cortisol. Decreased cortisol synthesis leads to elevated ACTH levels, which produces adrenal hyperplasia. Five different enzyme deficiencies can cause CAH, but deficiency of 21-alpha-hydroxylase accounts for more than 90% of cases. Impaired 21-hydroxylase activity causes deficient production of cortisol and aldosterone. Depending on the extent of the enzyme deficiency, CAH may present as either a salt losing (75% of cases) or a non-salt losing disorder during the newborn period. Both types of CAH are associated with genital abnormalities because 21-hydroxylase deficiency prevents precursor hormones, such as 17-hydroxyprogesterone (17-OHP), from entering the cortisol metabolic pathway. These precursors accumulate and spill over into the androgen metabolic pathway, forming androstenedione and testosterone. CAH screening is performed by measuring levels of 17-OHP in dried blood spots. Levels of < 50 ng/mL are considered normal for a normal weight infant of 2250 grams or greater. A significant problem with CAH screening programs, is that 17-OHP levels are elevated in very low birth weight (< 1500 grams) and extremely low birth weight (< 1000 grams) infants, resulting in many falsely positive results. Second Tier CAH testing is recommended for all newborns with abnormal 17-OHP screening results. Second tier testing by tandem mass spectrometry simultaneously measures 17-OHP, androstenedione and cortisol. Patients with CAH have elevated androstenedione and low or absent cortisol. Findings of elevated 17-0HP values (>10.2 ng/mL) and a high 17-OHP + androstenedione/cortisol ratio (>2.5) support the initial abnormal screening result. The Saint Luke's Hospital Reference Laboratory can be contacted at (816)932-2424 for further information or to obtain Mayo Medical Laboratories' blood spot collection cards. More information regarding newborn screening disorders is available at: http://www.dhss.mo.gov/Lab/Newborn/index.html |
||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||
|
||
 |
|
 |
|
|
|
 Neisseria GonorrhoeaeNeuropathy AntibodiesNewborn ScreeningNicotine & MetabolitesNTx TelopeptideNucleated Red Blood Cells |
|
|
|
 |
|
|
|
