NEWBORN SCREENING Greg Enns, MB, ChB, FAAP Professor of Pediatrics Director, Biochemical Genetics Program Lucile Packard Children’s Hospital October 22, 2015

Newborn Screening Goal 4/26/2017 Newborn Screening Goal The early detection of conditions for which early and timely interventions can lead to the elimination or reduction of associated mortality, morbidity and disabilities American Academy of Pediatrics Report Pediatrics 106:389, 2000

When is screening a good idea Condition Of medical importance, significant morbidity and/or mortality Natural history well understood Screening Test Safe, precise, validated test Treatment Effective treatment is available It is beneficial to start treatment early, before the onset of symptoms Cost-benefit Analysis The overall expense of the screening program is acceptable given the expected benefit to patients and families The social context The program, including testing, counseling and treatment is acceptable to the society in which it is being carried out

PHENYLKETONURIA (PKU) 4/26/2017 PHENYLKETONURIA (PKU)

Untreated PKU Mental retardation 4/26/2017 Untreated PKU Mental retardation Decreased deep tendon reflexes and spasticity Seizures Acquired microcephaly Pale pigmentation Dry skin Mousy odor (phenylacetic acid in urine and sweat)

PKU Newborn Screening Outcome 4/26/2017 PKU Newborn Screening Outcome

PKU Clinical Management 4/26/2017 PKU Clinical Management Regular appointments with the Metabolic “team” physician, nutritionist, genetic counselor, nurse, social worker Regular blood phenylalanine levels Once a week to once a month for the first 12 month (average once a week) Once a month to every 3 months throughout childhood

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History of Newborn Screening in California 4/26/2017 History of Newborn Screening in California 1966 - PKU 1980 - Hypothyroidism, Galactosemia 1990 - Sickle Cell Disease, other Hemoglobinopathies 2002 - 2003 - MS/MS Pilot Project 2005 - Expanded MS/MS screening

Current California Newborn Screening 4/26/2017 Current California Newborn Screening 550,000 Newborns per year (~1/8 of neonates born annually in USA) >99% screened

4/26/2017 THE “HEELSTICK TEST” Courtesey Dr. Ed McCabe

4/26/2017 Filter Card Punch Courtesey Dr. John Sherwin

Tandem Mass Spectrometry (MS/MS) Target Analytes for Newborn Screening 4/26/2017 Tandem Mass Spectrometry (MS/MS) Target Analytes for Newborn Screening Amino acids Acylcarnitines Intermediates of: Organic acids Fatty acids

Acylcarnitine Profile 4/26/2017 Acylcarnitine Profile Plasma/serum >30 compounds fatty acids organic acids Quick prep and run

4/26/2017 Acylcarnitines Acyl group of varying chain length attached to carnitine Acyl groups derived from organic acid metabolism and fatty acid oxidation Examples include: Octanoylcarnitine (C8-acylcarnitine) Propionylcarnitine (C3-acylcarnitine)

What is an acylcarnitine? 4/26/2017 What is an acylcarnitine? O = RC- O O = + (CH3)3N-CH2-CH-CH2-COO- Hexanoylcarnitine R = CH3(CH2)3CH2-

Normal Acylcarnitine Profile 4/26/2017 Normal Acylcarnitine Profile

MCAD Deficiency Acylcarnitine Profile 4/26/2017 MCAD Deficiency Acylcarnitine Profile Octanoylcarnitine

Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency 4/26/2017 Medium-chain Acyl-CoA Dehydrogenase (MCAD) Deficiency ~1/10,000 in Caucasians Sudden infant death syndrome Reye-like syndrome Episodic illness 6-24 months as a consequence of catabolism May have myopathy, cardiomyopathy Hypoketotic hypoglycemia

The primary energy source for: 4/26/2017 FATTY ACID METABOLISM The primary energy source for: Cardiac muscle Skeletal muscle A necessary energy source during: Fasting Stress

Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency 4/26/2017 Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency Retrospective analysis of original NBS sample Control LCHAD

Acylcarnitines (µM) in Original NBS Cards of LCHAD Deficient Patients 4/26/2017 Acylcarnitines (µM) in Original NBS Cards of LCHAD Deficient Patients Control C18:1 5000 m/z, amu cps Sample 4 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 8 C18:1 C16-OH C18-OH 5000 m/z, amu cps DEAD 5000 Sample 1 C18:1 C16-OH C18-OH m/z, amu cps Sample 5 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 9 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 2 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 6 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 10 C18:1 C16-OH C18-OH 5000 cps m/z, amu Sample 3 C18:1 C16-OH C18-OH 5000 m/z, amu cps Sample 7 C18:1 C16-OH C18-OH 5000 m/z, amu cps Control C18:1 5000 m/z, amu cps

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STATE TO EXPAND TESTING OF NEWBORNS FOR GENETIC ILLS 4/26/2017 STATE TO EXPAND TESTING OF NEWBORNS FOR GENETIC ILLS Newborns in California will soon get tested for more than 30 genetic illnesses that lead to serious health and developmental problems, a major increase in screening that will shore up the state's outdated protections for new babies.Gov. Arnold Schwarzenegger has already approved money for the new screening and is expected to sign the law finalizing it within the next two weeks. Most other states offer more newborn screening than California, which currently tests for only four. August 4, 2004, Page 1A, San Jose Mercury News (CA)

Communication in Newborn Screening 4/26/2017 Communication in Newborn Screening Private Sector Laboratories Central Laboratory Specialists: Biochemical Geneticist Endocrinologist Hematologist Area Service Center Family Primary Care Provider

Conditions Required – Sept, 2007 4/26/2017 34 34 14 35 16 46 50 50 33 34 54 50 44 49 45 49 45 31 51 13 25 43 14 50 41 46 33 45 46 50 31 47 31 37 31 52 DC 41 50 48 12 31 48 37 30 33 48 29 31 46 30 36 ‘Core’ 29 (21) 50+ Disorders U.S. Newborn Screening Conditions Required – Sept, 2007 40-49 Disorders 30-39 Disorders 20-29 Disorders genes-r-us 10-19 Disorders Courtesey of Dr. Brad Therrell

http://genes-r-us.uthscsa.edu

http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/

www.cdph.ca.gov

MS/MS Newborn Screening 4/26/2017 MS/MS Newborn Screening A normal screening result does not exclude metabolic disease

Optimal Path to Diagnosis 4/26/2017 Optimal Path to Diagnosis Urgent Referral Positive NBS Definitive Diagnosis To a geneticist or metabolic specialist Metabolite or enzyme assay diagnostic testing DNA testing Pediatricians should be aware of the unique signs and symptoms or clusters of common signs and symptoms that are suggestive of an LSD. If there is any clinical suspicion, the child should be urgently referred to a geneticist or metabolic specialist. Arriving at a definitive diagnosis is relatively simple. The gold standard is an enzyme assay performed on a blood sample. In some cases, DNA testing is performed as well.

SUMMARY Newborn screening does not detect everyone 4/26/2017 SUMMARY Newborn screening does not detect everyone Appropriate labs & investigations are needed to obtain final diagnosis A Uniform Screening Panel of 31 core disorders and 26 secondary disorders recommended by the DACHDNC has led to states testing for a similar number of disorders