Comprehensive Metabolic Screening UAE, Qatar, UAE, Bahrain, Oman, Saudi Arabia

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Value of Metabolic Disorder Screening for Newborns
Dr. Sanjida Ahmed (Director Research) Eastern
Biotech Life Sciences DuBiotech Park, Dubai
UAE Phone [phone] Email
sanjida_at_easternbiotech.com www.easternbiotech.com

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Tyler Waynes Story

• Tyler Wayne, was born 8 lbs. 3 oz. on May 1, 1998
  as a healthy baby
• At home he started vomiting violently and was
  admitted to the hospital again
• He was lethargic and was not responsive to any
  stimulation and taken to emergency
• Tyler died May 10th, 1998 on mothers day
• The results of his newborn screening showed a
  positive result for galactosemia- a metabolic
  disorder or Inborn Error of Metabolism (IEM)

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Metabolic Disorders/ IEM

• Metabolic disorders/IEMs are caused when the
  body is unable to break down nutrients, which
  then accumulate in the body and becomes toxic.
• When the concentration of toxic build-up
  increase they cross the blood-brain barrier and
  this leads to delayed development, brain damage
  and, in some cases, even death.
• Most infants with these disorders show no
  obvious signs of these disorders at birth, but
  the build-up can be rapid enough for the
  condition to become irreversible within a few
  weeks of birth.

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Reason behind these Disorders

• These disorders follow an autosomal recessive
  inheritance pattern
• Could skip generations
• Parents are carriers
• Happens when the two parents carry the gene 14
  probability of having an affected child

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Newborn Screening

• Newborn screening is the process of testing
  newborn babies for treatable genetic,
  endocrinologic, metabolic and hematologic
  diseases.
• Screening is done to assist healthcare providers
  in detecting the existence of a number of
  treatable but clinically undiagnosed disorders,
  before symptoms occur, so that the most
  beneficial outcome can be achieved.

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Diagnosis of Metabolic Disorders is Challenging

• The episodic nature of metabolic illness
• The wide range of clinical symptoms that are
  associated with more common conditions like
  infection or sepsis.
• The low incidence of these disorders
• The consequent lack of experience among the
  pediatric sub-specialties
• The need for specialty testing

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Early detection is very important

• Affected babies are identified quickly before
  symptoms appear.
• Cases of disease are not missed.
• The number of false-positive results is
  minimized.
• Early treatment can begin, that prevents the
  negative and irreversible health outcomes for
  affected newborns.
• Most treatments are inexpensive and may involve
  the addition of a vitamin to the diet, hormone
  supplementation, avoidance of certain foods and
  chemicals or a dietary change.

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If screening is delayed

• It could lead to lifelong complications
• Mental Retardation
• Motor Impairment
• Physical Disability

GA 1 Screened
GA 1 Screened
GA 1 Not Screened
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Benefits of Newborn Screening for Metabolic
Disorders
Newborn tested 24 Hours after birth
Positive
Negative
Negative
Confirmatory Test
Positive
Start Treatment
Absence of 50 treatable IEMs

• The newborn screen has to be done only once in a
  lifetime
• Speeds diagnosis and saves costs
• Healthy child instead of sick or mentally
  retarded child.

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Time to do screening

• Anytime 24 hours AFTER birth (ideally within 1-
  2 weeks).
• Baby needs to be fed at least 2 - 3 times before
  the specimen is taken.
• BEFORE developmental delay or other symptoms of
  mental retardation occur (best time is to screen
  a healthy baby).

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Every Newborn needs to be Screened

• Every Newborn (Routine screening)
• High Risk
• Unexplained deaths of siblings
• Miscarriages Aborted Fetuses
• Exhibit symptoms of IEMs
• Babies conceived by IVF
• Babies in NICU
• Sick Children

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Sample from babys Heel
1. Puncture heel
2. Lightly touch filter paper to LARGE blood drop
3. Dry the sample send to the laboratory
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Public Awareness of Metabolic Screening

• Newborn screening began in South Carolina in the
  mid-1960s with testing for phenylketonuria (PKU)
  only (Kidshealth.org)
• Over the years, the test panel has expanded with
  increased use of tandem mass spectrometry (MS/MS)
  in newborn screening applications
• Now almost all states screen for more
  than 30 disorders.
• (Kidshealth.org)
• Each year, at least 4 million babies in the
  United States are tested for these diseases, and
  severe disorders are detected in about 5,000
  newborns. (Kidshealth.org)

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Tandem Mass Spectrometry (MS/MS)

• Mass Spectrometry means multiple analyte
  testing
• Using Tandem Mass Spectrometry, multiple
  analytes are measured simultaneously
• Quantitatively measures amino acids and
  acylcarnitines from dried blood spot specimens
• Efficient and Economical
• MS/MS is very precise

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Expanded Newborn Screening

• ACYLCARNITINE PROFILE (Tandem Mass Spectrometry)
• Fatty Acid Oxidation Disorders
• Organic Acid Disorders
• AMINO ACID PROFILE (Tandem Mass Spectrometry)
• Amino Acid Disorders
• Others
• BIOCHEMICAL SCREENING (Enzyme Assay/Enz.
  immunoassay)
• Galactosemia
• Congenital Hypothyroidism
• Congenital Adrenal Hyperplasia
• G6PD Deficiency
• Cystic Fibrosis
• Biotinidase Deficiency

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Fatty Acid Oxidation Disorders (FAODS)

• Most common FA disorderMCADDis part of the
  current test panel
• Expansion added eleven FAO disorders
• Most are autosomal recessive disorders so risk of
  recurrence is 14 with each pregnancy

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Symptoms of Fatty Acid Oxidation Disorders

• Hypoketotic hypoglycemia
• Muscle weakness
• Seizures
• Sometimes cardiomyopathy

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Treatment of most Fatty Acid Oxidation Disorders

• Avoid fasting
• Immediate medical attention when unable to eat
  usual diet
• Control type/amount of fat in diet depending upon
  the specific diagnosis
• L-Carnitine if indicated
• Cornstarch tube feeding at night if indicated

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Organic Acid (OA) Disorders

• Expansion added the detection of 16 organic acid
  disorders
• Most are autosomal recessive disorders so risk of
  recurrence is 14 with each pregnancy
• A few sub-types are X-linked so only males are
  affected, but females may show milder symptoms

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Symptoms of most Organic Acid Disorders

• Feeding problems (feed intolerance)
• Seizures
• Metabolic acidosis
• Lethargy

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Treatment of most Organic Acid Disorders

• Avoid fasting
• Immediate medical attention when unable to eat
  usual diet
• Control type/amount of protein in diet depending
  upon the specific diagnosis
• Vitamin B12 if indicated

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Amino Acid (AA) Disorders

• Most common AA disorderPKUis part of the
  current test panel
• Expansion added additional 13 AA disorders
• All are recessive genetic disorders so risk of
  recurrence is 14 with each pregnancy
• Symptoms and treatments vary by disorder

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Biochemical Screening One test-One
Disorder(metabolic disorder screening that
cannot be performed by Tandem Mass Spectrometry)

• Galactosemia
• Congenital Hypothyroidism
• Congenital Adrenal Hyperplasia
• G6PD Deficiency
• Cystic Fibrosis
• BIotinidase Deficiency

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Future Direction

• Additional conditions are already under
  consideration for adding to screening panels
  SCID, lysosomal storage disease, fragile X
  syndrome and other
• Expansion of treatable disease criteria
• Considering the identification of unaffected
  carriers, or conditions

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Status of Newborn Screening in UAE

• The national neonatal screening program started
  by screening for phenylketonuria in January 1995
  (MOH, 2006)
• Screening for congenital hypothyroidism was
  introduced in January 1998 (MOH, 2006)
• By 2002, sickle cell anemia was identified by
  newborn screening program (MOH, 2006)
• In January 2005, Congenital Adrenal Hyperplasia
  has been included as part of the screening (MOH,
  2006)
• Screening for newborns is still not mandatory for
  each child born in UAE
• Only the sick babies are being tested due to a
  lack of awareness of the benefits and high costs

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Relative Incidence of disease

• Since the Implementation of the screening
  program, From Jan 1995
• until Dec 2005 by MOH (MOH, 2006)
• 385,135 infants were screened with the relative
  incidence of
• 1 1963 for congenital hypothyroidism, 188
  prevented from mental retardation
• 1 14,812 classic PKU, 26 prevented from mental
  retardation
• 0.06 for sickle disease and 0.9 for sickle cell
  traits

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Status of Newborn Screening in other GCC countries

• Aug 2005, National Newborn Screening started in
  Saudi Arabia, relative incidence of disorder is
  1758 (Study by NLNBS, 2005-2006)
• Implementation of National screening program
  including metabolic screening is under
  consideration in Bahrain
• Establish a national NBS program by using Tandem
  Mass Spectrometry is under consideration in
  Kuwait
• National newborn screening is yet to be
  established in Oman

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Barriers to Newborn Screening

• Cost of the screening and treatment
• Test cannot be done at birth (birth has to be in
  a hospital)
• Insufficient sampling due to the lack of proper
  training and education
• Difficult to reach in different geographic
  location
• Problems with recall and follow up cases

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Way Forward

• Governments need to take measures to make NBS
  mandatory for each and every baby born in the
  region
• Technical, Financial support and regional
  collaboration needed
• Consider Tendem Mass Spectrometry to widen the
  scope of the program
• Systematically evaluate all phases of the
  program including systemic evaluation of program
  data

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Conclusion

• All babies have equal right to live healthy lives
• We need to create the platform for them

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How does MS/MS work?
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How does MS/MS work?
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How does MS/MS work?

• A tandem mass spectrometer is simply 2 mass
  spectrometers hooked together with a special
  chamber between the 2 instruments
• After being prepped, the sample is injected into
  the first instrument.
• in the first instrument, the sample is ionized to
  produce molecular ions and the type of molecules
  present are determined based upon mass-to-charge
  (m/z) ratio
• The ionized molecules are sorted and weighed.
• Afterward, the sample is sent into the collision
  cell chamber.
• the molecular ion sample is broken into
  fragmented pieces, called analytes, in the
  collision cell chamber
• After being fragmented, the sample is passed into
  the second instrument where quantities of the
  selected analyte(s) are sorted and weighed
  according to their m/z ratio.
• The peak of each analyte is compared to internal
  standard to yield both a qualitative and
  quantitative result in computer

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If the child is older and no symptoms, parent
still want to test NBS

• Testing can be done at any age. Although many of
  the disorders will cause clinical symptoms at an
  early age, some may not show symptoms for months
  or years.
• It is important to screen all siblings, or to
  perform more specific diagnostic tests of
  siblings of any babies found to have one of these
  disorders.
• If the symptoms are there, this may not offer
  additional information but this will help them to
  discuss further with the pediatricians/genetic
  counselors

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What happens if baby is a carrier

• It is important for the parents to know if the
  baby is a CF carrier or has a hemoglobinopathy
  trait so they can
• tell their child later in life. His or her
  future partner can choose to have testing to
  identify the
• couples chances of having a baby with CF, or a
  clinically significant hemoglobinopathy.
• If the baby is a CF carrier or has a
  hemoglobinopathy trait, one parent is almost
  certainly a carrier. There is a small risk that
  both parents are carriers which would have
  implications for future pregnancies.
• Resources are available to assist in counseling
  families with regards to these issues.

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Critical steps for effective Newborn Screening

• Screening must be done soon after the birth
  (within 2 weeks)
• Initial follow-up of an abnormal value and
  repeat analysis needs to be done
• Confirmatory testing is required in case of
  repeated abnormal value
• Prompt referral of patients with confirmed or
  suspected disorders

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Resources for improved NBS program

• Clinical and biochemical geneticists
• Pediatric subspecialists
• Genetic counselors
• Metabolic dieticians
• Audiologists/Otolaryngologists

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Fatty acid oxidation pathway
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Organic acid disorder
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Amino acid disorder