The Best Kept SecretNC Newborn Screening Program

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The Best Kept SecretNC Newborn Screening Program

• Shu H. Chaing, Ph.D., DABCC
• Newborn Screening/Clinical Chem.
• NC State Lab. of Public Health

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What is Newborn Screening?
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• Genetic Testing to screen newborn for metabolic
  disorders.

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Why Do We Need Newborn Screening?

• To detect the health problems on the newborns
• To provide early diagnosis and treatment
• To prevent mental retardation, serious physical
  disabilities or death

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How and Where Are the Newborns Tested?

• A few drops of blood are collected from the
  babys heel before the baby leaves hospital
  nursery
• The blood specimen is collected on the Newborn
  Screening Form
• The blood specimen is then sent to Newborn
  Screening Laboratory for testing

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Newborn Screening Form

• Metabolic screening
• Hearing screening results
• Brief instruction
• Filter paper for blood collection

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Information Collected on Newborn Screening form

• General Information
• Medical record , Newborns name, Birth date
  time, race, sex, Mothers name, SS, address and
  telephone .
• Specific Information
• Birth weight
• Blood specimen collection date time
• Type of feeding Breast, Non-soy, Soy and
  parenteral
• Transfusion date time
• Health care providers (birthing hospital
  physician)

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Instruction for Blood Specimen Collection

• Obtain blood specimen from every infant before
  discharge or transfer.
• Optimum time for screening is 48-72 hours of age
• Blood specimens taken before 24 hours of age must
  be repeated within 7 days.
• Submit infants demographic data even when a
  blood specimen cannot be collected

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Instruction for Blood Specimen Collection

• Collect the specimen before the infant is
  transfused if possible. If not, a repeat
  specimen should be collected four months after
  the last transfusion.
• For very low birth weight infants (lt1500 g),
  retest should be done at 4-6 week of age.

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Newborn Screening Policy

• It is mandatory by law
• Parents can refuse newborn screening if contrary
  to their religious beliefs.

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What Are We Screening?

• A total of 30 disorders
• Galactosemia
• Biotinidase Deficiency
• Primary Hypothyroidism
• Congenital Adrenal Hyperplasia (CAH)
• Hemoglobinopathies
• Amino Acid Metabolism Disorders PKU others
• Fatty Acid Metabolism Disorders MCADD others
• Organic Acidurias PPA, IVA others

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Disorders Detected by Tandem Mass Spectrometry
(MS/MS)

• Amino Acid disorders
• Argininosuccinic aciduria (ASA)
• Citrullinemia (CIT I)
• Homocystinuria (cystathionine beta synthase)
  (HCY)
• Maple syrup urine disease / branched-chain
  ketoacid dehydrogenase (MSUD)
• Phenylketonuria / hyperphenylalaninemia (PKU)
• Tyrosinemia type II (TYR-II)
• Tyrosinemia type III (TYR-III)

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Disorders Detected by Tandem Mass Spectrometry
(MS/MS)

• Organic Acid Disorders
• Glutaric acidemia type I (GA-I)
• Multiple carboxylase deficiency (MCD)
• 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency
  (HMG)
• Isobutyryl-CoA dehydrogenase deficiency (IBD)
• Isovaleric acidemia / isovaleryl-CoA
  dehydrogenase (IVA)
• Beta-ketothiolase (BKT) / short-chain keto
  acylthiolase deficiency (SKAT)
• Methylmalonic aciduria (MMA)
• 2-Methylbutyryl-CoA dehydrogenase deficiency
  (2-MBD)
• 3-Methylcrotonyl-CoA carboxylase deficiency
  (3-MCC)
• Propionic acidemia (PPA, PROP)

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Disorders Detected by Tandem Mass Spectrometry
(MS/MS)

• Fatty Acid Disorders
• Carnitine/acylcarnitine translocase deficiency
  (CAT)
• Carnitine palmitoyltransferase II deficiency (CPT
  II)
• Medium-chain acyl-CoA dehydrogenase deficiency
  (MCAD)
• Multiple acyl-CoA dehydrogenase deficiency
  (GA-II)
• Long-chain 3-hydroxyacyl-CoA dehydrogenase
  deficiency (LCHAD)
• Short-chain acyl-CoA dehydrogenase deficiency
  (SCAD
• Trifunctional protein deficiency (TFP)
• Very long-chain acyl-CoA dehydrogenase deficiency
  (VLCAD)

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Causes of Clinical Symptoms

• Enzyme complex
• A-------------------------?B
• C
• Enzyme deficiency
• Accumulation of compound A
• Lack of production of compound B
• Alternative pathway, production of a toxic
  compound C

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Methodology for Detecting Metabolic Disorders

• For Screening Biochemical-based Methods
• For Confirmation DNA-based Methods

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Screening Methodology

• Metabolic pathway
• Enzyme
• A-----------------?B
• Can measure
• 1) Accumulation of compound A
• 2) Measure Enzyme activity

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• Phenylketonuria (PKU)
• Phenylalanine hydroxylase
• Phenylalanine----------------------?Tyrosine
• Galactosemia
• Gal ATP-------?Gal-1-P ADP
• Gal-1-P UDP-Glu--?UDP-Gal Glu-1-P
• Galactokinase Gal-1-P Uridyl Transferase

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Galactosemia

• NC Screening Began in Feb. 1988
• 140,000-60,000 Infants in NC
• High Blood Galactose
• Enzyme Deficiency Blocks the Metabolism of
  Galactose
• Clinical Symptoms Liver Dysfunction and Severe
  Sepsis within a Week After Birth
• Mental Retardation or Death if Untreated
• Treatment Restriction Dietary Therapy
  
  

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Biotinidase Deficiency

• NC Screening began in November 2004
• Complete deficiency 1 in 112,000
  Partial deficiency 1 in 129,000
• Little or no Biotinidase activity
• Enzyme deficiency blocks Biotin recycling
• Symptoms seizures, skin rash, hypotonia, hair
  loss, hearing loss, developmental delay, ataxia
  (defective muscular coordination)
• Treatment Biotin therapy

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Congenital Primary Hypothyroidism

• NC Screening Began in 1979
• 13,000-5,000 Infants Born in NC
• Low Thyroxine (T4) and High (Thyroid-Stimulating
  Hormone) TSH
• Occurs When the Thyroid Gland is Absent or not
  Functioning Properly
• Clinical Symptoms Difficult to Determine at
  Birth
• Mental Retardation or Death if Untreated
• Treatment Oral Thyroxine

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Congenital Adrenal Hyperplasia (CAH)

• NC Screening Began in 1989
• 120,000-25,000 Infants Born in NC
• High Blood 17-OH-Progesterone
• Enzyme Deficiency Blocks Normal Synthesis of
  Cortisol /Aldosterone
• Clinical Symptoms Ambiguous Genitalia / Salt
  Wasting
• Ambiguous Sex Characteristics / Death if
  Untreated
• Treatment Endocrine Therapy
• Testing FIA

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Hemoglobinopathies

• Targeted Screening July, 1987 Universal
  Screening May, 1994
• Sickle Cell Trait 1 in 12 African -Americans,
  Sickle Cell Disease 1 in 400 African -Americans
• Presence of Abnormal Hemoglobin or Abnormalities
  in Hemoglobin Synthesis
• Clinical Symptoms Sickle Cell Crisis, Leg
  Ulcers, Hand-Foot Syndrome, Slow Growth,
  Jaundice, Pain Joints, Stroke
• Treatment Oral Prophylactic Penicillin or
  Hydroxyuria

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Tandem Mass Spectrometry(MS / MS)

• Two mass spectrometers in tandem

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MS/MS Parent Ion Scanning

• Acylcarnitines (as butyl derivatives) share a
  common fragment ion at m/z 85 Da.
• The second mass analyzer is set to only detect
  am/z of 85
• Each time the second mass analyzer detects an ion
  with m/z of 85, the molecular ion in the first
  mass analyzer is recorded

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Impact of MS/MS Newborn Screening

• Can detect more disorders with one test and
  without increasing the cost

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Number of Disorder Screened

• 1966 Newborn Screening started, 1 disorder
• 1996 8 disorders
• 1997 30 plus disorders
• 25 of them are detected by MS/MS

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• Traditional Newborn Screening Test
• 1 Test---? 1 analyte---? 1 disorder
• Tandem Mass Spectrometry Screening
• 1 Test? Many Analytes? Many Disorders

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Impact of MS/MS Newborn Screening

• Can detect more disorders with one test and
  without increase in cost
• Have a better picture of the patients condition

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Impact of MS/MS Newborn Screening

• Can detect more disorders with one test and
  without increase in cost
• Have a better picture of the patients condition
• Create disparity among state newborn screening
  program

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• Disparity created in different states
• Some screen for 4 disorders while others screen
  for gt30 disorders
• Attempt to standardize Newborn Screening Panel
• March of Dime List 10 disorders
• ACMG List 29 disorders

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Impact of MS/MS Newborn Screening

• Can detect more disorders with one test and
  without increase in cost
• Have a better picture of the patients condition
• Create disparity among state newborn screening
  program
• Policy for adding new tests has been changed

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Criteria for Adding Disorders to Newborn
Screening Panel

• The disease must require treatment
• The treatment must be available
• The diagnosis must be difficult to make without
  testing
• The testing must be cost effective
• Parents demand MS/MS newborn screening even some
  of the disorders are not treatable

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Tandem Mass Spectrometry

• Can detect
• Amino Acid Metabolism Disorders
• ExamplesPhenylketonuria ( PKU)
• Fatty Acid Metabolism Disorders
• Examples Medium-Chain Acyl CoA Deficiency
  Disorder (MCADD)
• Organic Acidurias
• Examples Propionic Acidemia (PPA), Isovaleric
  Acidemia (IVA)

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Phenylketonuria (PKU)

• NC screening began in 1966
• 110,000-20,000 infants born in NC
• High blood phenylalanine
• Clinical symptoms difficult to determine at
  birth
• Mental retardation or death if untreated
• Treatment Restriction dietary therapy

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Medium-Chain Acyl CoA Dehydrogenase (MCAD)
Deficiency

• NC screening began in April 1999
• 113,000 infants born in NC
• High medium-chain acylcarnitines (C6, C8 C8/C10
  ratio)
• Symptoms episodic and triggered by common
  illness or fasting. Hypoketotic hypoglycemia,
  vomiting, lethargy, liver disease, coma or death

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Medium-Chain Acyl CoA Dehydrogenase (MCAD)
Deficiency

• 1/3 die with initial presentation, 1/3 have long
  term neurological disabilities, 1/3 remain
  asymptomatic
• Prognosis is good, especially when treatment
  begins prior to the first metabolic crisis.
• Treatment avoid fasting, low-fat diet,
  supplement with carnitine

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Two Tier Approach for Cut offs and Follow up
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Follow up

• After testing, two copies of result report for
  each baby will be sent to birthing hospital and
  the babys doctor
• Can obtain results via web site reporting, 24
  hours a day and 7 days a week
• If abnormal results, the babys doctor and
  parents will be contacted for repeat testing or
  refer to specialist for diagnosis and treatment.
• Most newborn are born healthy and normal and will
  not hear from usWhich is good news!

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Incidence of Other Disorders (2006)

• Disorders of Cases Incidence
• Hypothyroidism 67 11,898
• CAH 4 131,794
• Galactosemia 4 131,794
• Biotinidase Def. 2 163,589
• Sickle Cell 117 11,087
• Hb Traits 3,582 136

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History of NC Newborn Screening Program

• 1966 - PKU
• 1979 - Primary Hypothyroidism
• 1987 - Hemoglobinopathies (Targeted)
• 1988 - Galactosemia
• 1989 - Congenital Adrenal Hyperplasia (CAH)
• 1994 - Hemoglobinopathies (Universal)
• 1997 - Tandem Mass Spectrometry (Pilot)
• 1999 - Tandem Mass Spectrometry (In House)
• 2004 - Biotinidase Deficiency