Learning Objectives
• Standard Neonatal screening state by state,
• Describe TMS methods
• What disorders can TMS screen for?
Pre-test Questions
- Which of the following is a common reason for genetic testing?
- Family Hx
- Age of the mother
- Premature delivery of the infant
- Racial profile
- All of the above
- Tandem Mass Spec is a method using:
- Blood
- Saliva
- Amniotic Fluid
- Meconium
- What are the most common genetic disorders tested for in the US?
- Cystic Fibrosis
- Sickle Cell Anemia
- PKU
Case: Mrs. Jones comes to your pediatric office with her two week old child. She is interested in benefits of extended neonatal screening and is wondering whether this is an appropriate choice for her son, if there is extra cost and whether it will be worth the cost to her. She and her son live in Kentucky. As far as she knows there is no family history of any genetic diseases in the family, and she had an uncomplicated pregnancy, with an uncomplicated birth of a healthy boy with APGARS of 8 and 9 after spontaneous vaginal delivery. Beyond the routine screening, how would you advise this woman?
QUESTIONS:
- What has this baby already been tested for at birth as required by the state of Kentucky?
Kentucky requires screening for the following diseases:
1 Congenital Hypothyroidism (CH)
2 Galactosemia
3 Phenylketonuria (PKU)
4 Sickle Cell Disease (SCD) and Hemoglobinopathie
The 2005 General Assembly passed legislation to expand to the full panel of the 28 disorders (plus hearing screening) recommended by ACMG/HRSA and to establish ongoing funding for the newborn screening program. Implementation is occurring by a six-month rollout from July 1 through December 31, 2005. It is anticipated that Kentucky will be screening for all of these 28 disorders (plus hearing screening) by January 1, 2006.
2.What are the risks associated with non-detection of metabolic, amino acid and other screened for disorders?
The impetus for newborn screening rests on the learning that there are many genetic disorders that while may not affect the newborn at birth or be detected upon physical exam, may cause changes as the child develops leading to complication such as mental retardation and death, including SIDS (Sudden infant Death Syndrome). Newborn screening aims to pick up these disorders and implicate prevention and treatment methods in these children to give them the best possible outcome.
3. What is Tandem Mass Spectrometry and how has it changed newborn screening?
Before TMS, newborm screening was limited by needing to use separate bacterial assays to evaluate for different metabolic, amino acid and other genetically inherited disorders, and by factors affecting sampling from the newborn including method of collection type of sample (blood, urine). There was no simple, effective technology that could rely on the collection of one sample to screen for a number of diseases at one time until the advent of TMS.
Mass spectrometers electronically weigh molecules in a sample as a means to identifying them. A tandem mass spectrometer can be thought of as two mass spectrometers in series connected by a chamber that can break a molecule into pieces perhaps like a puzzle. This chamber is known as a collision cell. A sample is “sorted” and “weighed” in the first mass spectrometer, then broken into pieces in the collision cell, and a piece or pieces sorted and weighed in the second mass spectrometer. The blood samples that we screen hundreds of compounds in them, but we are interested in only a few dozen. It is not practical to identify every compound in the samples that we receive, so we look for compounds of interest to us that have diagnostic significance. Fortunately, the compounds in the blood samples that we analyze have certain common and unique characteristics. These compounds are members of a chemical class or family such as amino acids or fatty acids .
4.What sample is needed from the baby?
At birth, a simple heel stick from the baby, usually done by the nurse in the delivery room, is used and the drop of blood from the baby is put onto special paper that can then be used in the TMS for the electronic weighing.
5. What are the disorders detected by the TMS?
Disorders Detected by Tandem Mass Spectrometry
Fatty Acid Oxidation Disorders
Carnitine/Acylcarnitine Translocase Deficiency (Translocase)
Carnitine Palmitoyl Transferase Deficiency Type I (CPT-I) 2
3-Hydroxy Long Chain Acyl-CoA Dehydrogenase Deficiency (LCHAD)
2,4-Dienoyl-CoA Reductase Deficiency 2
Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD)
Multiple Acyl-CoA Dehydrogenase Deficiency (MADD or Glutaric Acidemia-Type II)
Neonatal Carnitine Palmitoyl Transferase Deficiency-Type II (CPT-II)
Short Chain Acyl-CoA Dehydrogenase Deficiency (SCAD)
Short Chain Hydroxy Acyl-CoA Dehydrogenase Deficiency (SCHAD)
Trifunctional Protein Deficiency (TFP Deficiency)
Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCAD)
Organic Acid Disorders
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (HMG)
Glutaric Acidemia-Type I (GA I)
Isobutyryl-CoA Dehydrogenase Deficiency
Isovaleric Acidemia (IVA)
Acute onset
Chronic
2-Methylbutryl-CoA Dehydrogenase Deficiency
3-Methylcrotonyl-CoA Carboxylase Deficiency (3MCC Deficiency)
3-Methylglutaconyl-CoA Hydratase Deficiency
Methylmalonic Acidemias
Methylmalonyl-CoA Mutase Deficiency 0
Methylmalonyl-CoA Mutase Deficiency +
Some Adenosylcobalamin Synthesis Defects
Maternal Vitamin B12 Deficiency
Mitochondrial Acetoacetyl-CoA Thiolase Deficiency (3-Ketothiolase Def.)
Propionic Acidemia (PA)
Acute onset
Late onset
Multiple-CoA Carboxylase Deficiency
Malonic Aciduria 2
Amino Acid Disorders
Argininemia
Argininosuccinic Aciduria (ASA Lyase Deficiency)
Acute onset
Late onset
Carbamoylphosphate Synthetase Deficiency (CPS Def.)2
Citrullinemia (ASA Synthetase Deficiency)
Acute onset
Late onset
Homocystinuria (Hypermethioninemia)
Hyperammonemia, Hyperornithinemia, Homocitrullinemia Syndrome (HHH) 2
Hyperornithinemia with Gyral Atrophy 2
Maple Syrup Urine Disease (MSUD)
Classical MSUD
Intermediate MSUD
5-Oxoprolinuria (pyroglutamic Aciduria) 2
Phenylketonuria (PKU)
Classical PKU
Hyperphenylalaninemia
Biopterin Cofactor Deficiencies (4)
Tyrosinemia
Transient Neonatal Tyrosinemia
Tyrosinemia Type I (Tyr I) 2
Tyrosinemia Type II (Tyr II)
Tyrosimenia Type III (Tyr III)
Other Abnormal Profiles
Hyperalimentation
Liver Disease
Medium Chain Triglyceride (MCT) Oil Administration
Presence of EDTA Antigoagulants in blood specimen
Treatment with Benzoate, Pyvalic Acid, or Valproic Acid
6. Why are the measurements of amino acids and acylcarnitines important?
In inherited metabolic diseases, specific enzymes (catalysts) that helps facilitate the breakdown of amino acids or the conversion of fat to energy do not function. If a particular enzyme is not functioning, the breakdown of a compound by this enzyme (metabolism) to waste products does not occur. In other instances, products are not produced that are important in generating fuel for the cell. Because the compound can not be metabolized, it will accumulate in the blood and tissues. The compound in excess then becomes a poison rather than a “normal substance.” The tandem mass spectrometer, by measuring the amounts of amino acids or acylcarnitines in blood, can tell us using special computer software and expert medical interpretation, whether there is too much of the compound that we analyzed in the blood. This information is communicated to the pediatrician and together with other information will indicate what additional tests are needed to confirm the presence of an inherited disease. If confirmed, treatment of the inherited disorder is started. Treatment of these diseases most often involves changes in the diet that may include fat or protein restriction and/or special vitamin supplements. The pediatrician will probably collect blood samples occasionally to insure that a normal body chemistry is restored and if not, whether the diet must be changed to increase or decrease protein or fat intake. One in 1,500 babies born is affected by an inherited disorder that can be detected through newborn screening. Screening, diagnosis, and intervention within the first days of life are essential because many of these disorders are manageable if treatment begins early.
Who pays for the newborn screening, and how much does it cost to get extra testing?
Each state had different insurance policies and public benefit programs that cover varying amounts of the cost for screening. In this case, if Mrs. Jones is interested in genetic testing beyond the basic screening required by the state of Kentucky she would likely have to purchase a screening kit, such as the one available from Pediatrix, and have the hospital coordinate testing with Pediatrix. Just as an example of the extra cost incurred by purchasing these kits and using them at birth, the Pediatrix kit is $89.99 and information about the kit and how to coordinate with the hospital can be found at their website. There are other companies that offer testing, and those suggested by Kentucky can be found on the Kentucky Governnment info on newborn screening mentioned below.
Resources:
A layperson's guide to Tandem Mass Spectrometry and Newborn Screening
Written By Dr. Donald H. Chace, Ph.D., M.S.F.S. Retrieved on http://www.savebabies.org/screeninginformation.php
Levy, Harvey . Newborn Screening by Tandem Mass Spectrometry: A New Era. Clinical Chemistry 44:2401-2402, 1998
Save Babies.ORG Foundation Website:
http://www.savebabies.org/screeninginformation.php
Kentucky State Government Website on State Screening Policy:
http://chfs.ky.gov/dph/ach/newbornscreening.htm
NNSGRC- National Newborn Screening and Genetics Resource Center:
http://genes-r-us.uthscsa.edu/
Pediatrix Medical Group Newborn Screening Information: http://www.pediatrix.com/body_screening.cfm?id=222&oTopID=94
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