Value of Metabolic Disorder Screening for Newborns

Dr. Sanjida Ahmed (Director: Research)Eastern Biotech & Life Sciences

DuBiotech Park, Dubai UAEPhone: 00971 4 3692061

Email: sanjida@easternbiotech.com

www.easternbiotech.com

Tyler Wayne’s 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 mother’s day

• The results of his newborn screening showed a positive result for galactosemia- a metabolic disorder or Inborn Error of Metabolism (IEM)

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.

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 1:4 probability of having an affected child

Newborn ScreeningNewborn 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.

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

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.

If screening is delayedIt could lead to lifelong complications:

• Mental Retardation

• Motor Impairment

• Physical Disability

GA 1 Screened

GA 1 Not Screened

GA 1 Screened

Newborn tested 24 Hours after birth

Confirmatory Test

Start Treatment

Positive

Absence of 50 + treatable IEMs

Positive

• 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.

NegativeNegative

Benefits of Newborn Screening for Metabolic Disorders

• 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).

Time to do screening

• Every Newborn (Routine screening)

• High Risko Unexplained deaths of siblingso Miscarriages & Aborted Fetuseso Exhibit symptoms of IEMso Babies conceived by IVFo Babies in NICU

• Sick Children

Every Newborn needs to be Screened

Sample from baby’s Heel

1. Puncture heel

2. Lightly touch filter paper to LARGE blood drop

3. Dry the sample & send to the laboratory

Public Awareness of Metabolic Screening

• Newborn screening began in South Carolina in the mid-1960’s 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)

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

Expanded Newborn Screening• ACYLCARNITINE PROFILE (Tandem Mass Spectrometry)1. Fatty Acid Oxidation Disorders2. Organic Acid Disorders• AMINO ACID PROFILE (Tandem Mass Spectrometry)1. Amino Acid Disorders2. Others• BIOCHEMICAL SCREENING (Enzyme Assay/Enz. immunoassay)1. Galactosemia2. Congenital Hypothyroidism3. Congenital Adrenal Hyperplasia4. G6PD Deficiency5. Cystic Fibrosis 6. Biotinidase Deficiency

Fatty Acid Oxidation Disorders (FAODS)

• Most common FA disorder—MCADD—is part of the current test panel

• Expansion added eleven FAO disorders

• Most are autosomal recessive disorders so risk of recurrence is 1:4 with each pregnancy

Symptoms of Fatty Acid Oxidation Disorders

• Hypoketotic hypoglycemia

• Muscle weakness

• Seizures

• Sometimes cardiomyopathy

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

Organic Acid (OA) Disorders

• Expansion added the detection of 16 organic acid disorders

• Most are autosomal recessive disorders so risk of recurrence is 1:4 with each pregnancy

• A few sub-types are X-linked so only males are affected, but females may show milder symptoms

Symptoms of most Organic Acid Disorders

• Feeding problems (feed intolerance)

• Seizures

• Metabolic acidosis

• Lethargy

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

Amino Acid (AA) Disorders• Most common AA disorder—PKU—is part of the current

test panel• Expansion added additional 13 AA disorders• All are recessive genetic disorders so risk of recurrence is

1:4 with each pregnancy• Symptoms and treatments vary by disorder

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

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

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

Relative Incidence of disease

Since the Implementation of the screening program, From Jan 1995until 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

Status of Newborn Screening in other GCC countries

• Aug 2005, National Newborn Screening started in Saudi Arabia, relative incidence of disorder is 1:758 (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

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

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

Conclusion

All babies have equal right to live healthy lives&

We need to create the platform for them

How does MS/MS work?

How does MS/MS work?

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

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

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: 1. tell their child later in life. His or her future partner can choose to have

testing to identify the 2. couple’s 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.

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

Resources for improved NBS program

• Clinical and biochemical geneticists

• Pediatric subspecialists

• Genetic counselors

• Metabolic dieticians

• Audiologists/Otolaryngologists

Fatty acid oxidation pathway

Organic acid disorder

Amino acid disorder