1. The Expanding Expanded Newborn Screen R. A. Heidenreich, MD Professor of Pediatrics Division of Pediatric Genetics The University of New Mexico

2. Expansion of Testing Historically, the blood was tested for accumulated products of abnormal metabolites –Phenylalanine was the first disorder tested beginning in the 1960s but slowly more disorders were added Prior to about 5-10 years ago (depending on which state) the number of disorders tested for was 4-8 With the technologic advance of tandem mass spectrometry, the number of disorders able to be assayed increased significantly.

3. Mass Spectrometry Small sample from the original newborn screening card Blood extracted and compounds derivatized to make more volatile Injected into the MS/MS machine, ionized, sent through varying magnetic fields that separates molecules based on mass and charge Molecule is also fragmented and gives a very specific detection pattern

4. March of Dimes and ACMG Two organizations have attempted to codify a uniform panel of diseases for newborn screening –29 disorders including newborn hearing –However, because of the ability of MS/MS to detect even more disease, there is debate about adding even more disorders New Mexico is following these recommendations However, because of the expense of the instruments, all samples are sent to Oregon for analysis

5. Categories of Disorders Amino acid disorders –Phenylketonuria, tyrosinemia, citrullinemia, and argininosuccinic aciduria Organic acid disorders –Maple syrup urine disease, propionic acidemia, methylmalonic acidemia, fatty acid oxidation disorders Carbohydrate disorders –Galactosemia

6. Categories of Disorders Vitamin disorders –Biotinidase deficiency Endocrine disorders –Congenital hypothyroidism, congenital adrenal hyperplasia Hematologic disorders –Hemoglobinopathies Sickle cell disease Congenital Deafness Cystic Fibrosis

7. Present Testing Methods Tandem Mass Spectrometry –For all of the amino acid and organic acid disorders Biotinidase –Colorimetric assay of biotinidase activity Galactosemia –Colorimetric assay of galactose-1-phosphate uridyltransferase activity Congenital hypothyroidism –T 4 and, if abnormal, TSH levels

8. Present Testing Methods CAH –17-OH progesterone assay Hemoglobinopathies –Hgb electrophoresis Cystic fibrosis –Trypsinogen levels –DNA analysis Deafness –Acoustic emissions in the hospital

9. Disorders Phenylketonuria Classical form Mild hyperphenylalaninemia Untreated, it causes severe mental retardation, seizures. Dietary restriction of phenylalanine is a highly effective treatment and children, if well-treated, are normal. Tyrosinemia –Type I most severe and causes severe liver failure in the first year of life. –Treatable with Orfadin ® (NTBC) and dietary protein restriction –May still require liver transplantation later in life (increased risk of hepatic cancer)

10. Disorders, cont. Homocystinuria –Mental retardation, ocular lens dislocation, Marfanoid body habitus –Treat with dietary protein restriction Urea cycle defects: citrullinemia and argininosuccinic aciduria –There are other urea cycle defects but testing MS/MS not yet applicable –Severe hyperammonemia –Dietary protein restriction, medications

11. Disorders, cont. Organic acidemias –Maple syrup urine disease Very dangerous disorder that presents in the first week of life Treat with dietary protein restriction –Fatty acid oxidation defects MCAD is most common and may present with hypoglycemia and Reye-like symptoms –Many others:SCAD, LCAD, LCHAD, SCHAD, VLCAD, carnitine deficiency Treat by avoidance of fasting and carnitine supplementation –Other organic acid disorders Propionic, methylmalonic, HMG-CoA lyase, 3-MCC –Acidosis, seizures Treat by dietary protein restriction, alkali therapy and avoidance of fasting

12. Disorders, cont. Biotinidase deficiency –Causes biotin deficiency beginning at about 4-6 months of life –Dermatitis, alopecia, acidosis, neurologic impairment –Treat with 5-10 mg of biotin a day Galactosemia –Hyperbilirubinemia, hepatitis, cataracts, hypoglycemia, urine reducing substances –Treat with lactose-restricted diet

13. Disorders, cont. Congenital hypothyroidism –Mental retardation, constipation, failure to thrive –Treat with thyroxine supplementation Congenital adrenal hyperplasia –21-hydroxylase deficiency –Salt wasting in males Severe hyperkalemia –Virilization in females –Treat with corticosteroids and mineralocorticoids

14. Disorders, cont. Hemoglobinopathies –Detect sickle cell disease and variants –Penicillin prophylaxis Cystic Fibrosis –Assurance of proper nutrition and medications Congenital Deafness –Not done from the blood spot, of course –Treat with early intervention strategies to improve communication skills SCID –Analysis for T-cell receptor excision circles (TRECs) –Reported higher incidence in Navajo population

15. The Expanding Expanded Screen Lysosomal storage disorders –Enzyme replacement therapy –HB201 (2010)

16. HB201 Passed in the NM Legislature New disorders will eventually be added to the NM newborn screen –Pompe disease –Krabbe disease –Gaucher disease –Niemann-Pick disease –Fabry disease The reason for adding to the screen is the availability of enzyme replacement therapy or bone marrow transplantation NM will likely have to wait for Oregon to add these same tests

17. Gaucher disease Lysosomal storage disorder due to defective function of glucocerebrosidase Different presentation ages –Severe infantile form with neurodegeneration –Intermediate childhood form with some neurologic symptoms –Very common adolescent and adult form Splenomegaly Thrombocytopenia Bone crises Treated very effectively for over a decade with enzyme replacement therapy –Cerezyme –Velaglucerase

18. Fabry disease Lysosomal storage disorder due to defective function of alpha-galactosidase A Characterized by accumulation of globotriaosylceramides –Occurs in the endothelial cells –Causes blood vessel involvement –Strokes, renal disease, cardiac disease, peripheral neuropathy Effective treatment with ERT –Fabrazyme

19. Pompe disease –Glycogen storage disease type II –Lysosomal acid maltase deficiency –Infantile form Severe cardiomyopathy –Childhood and adult forms Skeletal myopathy Highly effective treatment with enzyme replacement therapy –Lumizyme

20. Niemann-Pick disease Types A and B due to defective function of sphingomyelinase Types C and D due to defective cholesterol trafficking The newborn screen will be for types A and B by detecting abnormal sphingomyelinase activity –Types C and D may be picked up due to somewhat reduced activity ERT treatment is still in the research phase but an is coming –BMT has been effective in some cases

21. Krabbe disease Also known as globoid cell leukodystrophy Defective activity of lysosomal galactocerebrosidase Degenerative neurologic disorder with a leukodystrophy Buffalo Bill quarterback Jim Kelley had a child with the disorder Early diagnosis enables bone marrow transplantation

22. What About Others? Effective ERT and BMT exists for the mucopolysaccharidoses MPS1 –Hurler, Hurler-Scheie and Scheie –Aldurazyme MPS2 –Hunter syndrome –Elaprase MPS VI –Maroteaux-Lamy –Naglazyme Assay for enzymes in blood spots problematic

23. What About Others? Spinal muscular atrophy –Fairly common deletion of exons 7 and 8 in SMA1 Fragile X syndrome –Definite research showing that detection of the trinucleotide repeat is feasible from the blood spot Other DNA based testing

24. Resources –NM Newborn Screening http://www.nmhealth.org/about/phd/fhb/cms/nbgs/www.nmhealth.org/about/phd/fhb/cms/nbgs/ –Oregon Newborn Screening http://public.health.oregon.gov/LaboratoryServices/NewbornS creening/Pages/index.aspxhttp://public.health.oregon.gov/LaboratoryServices/NewbornS creening/Pages/index.aspx –March of Dimes http://www.marchofdimes.com/professionals/14332_1200.asp –Save Babies http://www.savebabies.org/ –Newborn Screening ACT Sheets http://www.ncbi.nlm.nih.gov/books/NBK55827/