16. neonatal screening

8/7/2019 16. NEONATAL SCREENING

http://slidepdf.com/reader/full/16-neonatal-screening 1/50

NEONATAL SCREENING



DEFINITION

Newborn screening is the process of testingnewborn babies for treatable genetic

,endocrinologic, metabolic and hematologicdiseases. Newborn screening has been

adopted by most countries around theworld, though the lists of screened diseasesvary widely, anywhere from 1 disorder tomore than 100 disorders.



GOALS

The AIM of population screening of neonates is to identify individuals with

increased probability of having thoseconditions which are not easily detectedclinically, and for which diagnosis and earlyinitiation of treatment are necessary toprevent, delay or ameliorate considerabledisability or serious disease.



Premise of newborn screening

To be included as a primary target, a conditionshould meet the following minimum criteria:

It can be identified at a phase (24 to 48 hours after

birth) at which it would not ordinarily be clinically

Detected

There are demonstrated benefits of early detection,

timely intervention and efficacious treatment of the

condition being testedA test with appropriate sensitivity and specificity is

available for it



Common considerations in determining whether toscreen for disorders:

A disease that can be missed clinically at birth

A high enough frequency in the population

A delay in diagnosis will induce irreversible

damages to the baby A simple and reasonably reliable test exists

A treatment or intervention that makes adifference if the disease is detected early



According to the U.S.(CDC) 3,000 babies with

severe disorders are identified in the UnitedStates each year using newborn screeningprograms at current testing rates.

The first test to be universally mandated across

the U.S. was the Guthrie test forphenylketonuria( PKU), and in many areas and hospitals, thenewborn blood test is often erroneouslyreferred to as a "PKU test

All states now universally test for congenitalhypothyroidism, galactosemia, and increasingnumbers of other diseases as well.



Endocrine disorders:Congenital adrenal

hyperplasia (CAH),Congenital hypothyroidism Blood cell disorders: sickle-cell disease (SS)

Inborn errors of carbohydrate metabolism:Galactosemia

Inborn errors of amino acid metabolism:Phenylketonuria (PKU), Maple syrup urinedisease (MSUD), Homocystinuria

Inborn errors of organic acid metabolism:

Biotinidase deficiency



The only tests mandated in every state arethe following:

CH -Congenital hypothyroidism

H-HPE

- Benign hyperphenylalaninemia PKU:

Phenylketonuria/hyperphenylalaninemia

HEAR - Hearing

GALT -Transferase deficientgalactosemia



Mandated tests ² NE, IA

Phenylketonuria (PKU) (1:20,000) Biotinidase deficiency (1:90,000)

Galactosemia (1:60,000)

Congenital hypothyroidism (CH) (1:3,350)

Congenital adrenal hyperplasia (CAH)(1:13,500)

Cystic fibrosis (CF) (1:4500)

Hemoglobin variants (S disease: 1:400 AA)

Medium chain acyl-CoA dehydrogenase

deficiency (MCADD) (1:17,000)



Newborn screening ² the basics

Prosedures

Filter paper bloodspot samples are used

Bloodspots are used for screening test

Collection timing is important for some analytes

24-hour sample is standard collection

Confirmation testing is required for positives

for positive identification

for possible false positives

for possible partial deficiencies

Cutoffs are conservative favoring sensitivity



Phenylketonuria

Autosomal recessive disorder caused by thelack of phenylalanine hydroxylase, theenzyme that converts the amino acidphenylalanine to tyrosine

Prevalence: 1:20,000 Without early diagnosis and strict adherence

to a special diet, brain damage and mental

retardation can occur Phenylalanine is present in almost all foods



Phenylketonuria

Screening: measure PHE after 24 hours measured by mass spectrometry elevated PHE presumed positive

Treatment: diet restricted in PHE restricted diet maintained through adolescence important also to restrict PHE during PKU

pregnancy



Biotin and Biotinidase

Biotin (Vitamin H) is a molecule needed for

activation of four carboxylases

e.g., pyruvate-oxaloacetate carboxylase neededfor gluconeogenesis

Biotin comes from diet

Biotinidase is an enzyme necessary to recycle

biotin




Inherited disorder

Prevalence: 1:90,000

Symptoms: two weeks to two years of age

seizures, low muscle tone, developmental delay,hearing loss, vision problems and recurrent

infections.

Early treatment with biotin supplementation

results in normal growth and development



Screen: measure biotinidase activity

substrate to product reaction coupled to color

change low product = presumed positive

Treatment: biotin supplementation

simple, successful treatment




Galactosemia

Autosomal recessive disorder

Primary form is a deficiency of GALT

galactose-1-phosphate uridyl transferase enzyme needed to break down the milk sugar

lactose


Life-threatening galactosemia, mentalretardation, and blindness can occur

Clinical symptoms may present as early asthe first week of life.



Galactosemia

Screening test: substrate to product reaction

requiring GALT, coupled to fluorescent

endpoint non-fluorescence = presumed positive

Treatment: eliminate dietary lactose,galactose

no breastfeeding

simple, effective treatment



Congenital hypothyroidism

Deficiency in the production of thyroid

hormone

Prevalence: 1:3,350 Poor growth, mental retardation, deafness

and neurological abnormalities can result

without prompt identification and treatment.

Early diagnosis and adequate treatment withthyroxine within the first weeks of life results

in normal growth and intelligence.



Congenital hypothyroidism

Screening test

Immunoassays forT4,TSH

lowT4, elevatedTSH = presumed positive positive is with respect to primary

hypothyroidism

Treatment Thyroxine replacement



Congenital adrenal hyperplasia

A group of inherited disorders caused byabnormalities in specific enzymes of the adrenalgland

Ninety percent of congenital adrenal hyperplasiacases arecaused by the lack of the enzyme steroid21-hydroxylase


Babies with untreated congenital adrenal

hyperplasia may develop vomiting and severedehydration (aldosterone deficient, salt-wastingCAH), which can be life threatening

Increased production of androgens can result inambiguous genitalia in infants



Congenital adrenal hyperplasia

Screening test

immunoassay for 17-OH-progesterone

elevated 17-OH-P = presumed positive Treatment

androgen suppression

cortisol replacement/endocrine monitoring



Hemoglobinopathies

Inherited red blood cell disorders caused byabnormalities in the structure or production of hemoglobins

Sickle cell anemia (S disease) is one of the mostcommon hemoglobinopathies Prevalence: 1:400 in African-Americans

red blood cells sickle and clog small vessels, disrupting thedelivery of oxygen to the body tissues.

Sickle cell anemia can cause pain, infection, lungcomplications, gallstones, stroke and other medicalproblems.

Antibiotics can minimize life-threateningcomplications.



Cystic Fibrosis (mucoviscidosis)

Autosomal recessive disorder characterized bypulmonary obstruction and/or exocrinepancreatic dysfunction

Prevalence: 1:4500 Mutations are of Cystic FibrosisTransmembrane

Regulator (CFTR) gene (chloride ion channel)

The major (70%) and most severe geneticmutation is a three-basepair deletion (F508) gene product does not reach membrane

nonfunctional



Cystic Fibrosis - IRT

Immunorective trypsinogen (IRT) produced in the pancreas and transported to the

intestine, where it is activated to form the enzyme

trypsin. InCF, thick mucus plugs can obstruct pancreatic ducts

and prevent trypsinogen from reaching the intestine. IRTwill be elevated in newborns with CF, but positive

results must be followed by confirmatory testing as there

is a high rate of false positive IRTs (positives due toconditions other thanCF and/or temporary elevations)

Confirmation may involve a sweat test for elevatedchloride



Cystic Fibrosis

Screening test

immunoassay for IRT

elevated IR

T= presumed positive

PCR check for F508 deletion mutation

expanded PCR mutation panel (99% sensitivity)

Treatment

medical care for nutrition, pancreatic enzymereplacement, infections

outcomes? states interest?



Medium chain acyl-CoA dehydrogenase deficiency

Inherited disorder of fatty acid oxidation(FAO)

enzyme required to convert fat into energy

F

AO provides acetyl-C

oA to Krebs cycle Prevalence: 1:17,000

free fatty acids mobilized by hormonal

activity during fasting

defects present as acute, life-threatening

episodes of hypoketotic, hypoglycemic coma

induced by fasting



MCAD Deficiency

Screening test

by mass spectrometry

measure acylcarnitine profile

elevatedC8-acylcarnitine = presumed positive

Treatment

careful, critical avoidance of prolonged fasting



MS/MS - Fatty Acid Oxidation Defects

Carnitine PalmitoylTransferase DeficiencyType l (CPT-1)

Carnitine PalmitoylTransferase DeficiencyType ll (CPT-2)

Carnitine/Acylcarnitine Translocase Deficiency (CAT)

Long-Chain hydroxy Acyl-CoA Dehydrogenase Def (LCHAD)

Multiple Acyl-CoA Dehydrogenase Deficiency GA-II

Short-Chain Acyl-CoA Dehydrogenase Def. (SCAD)

Short-Chain Hydroxy Acyl-CoA Dehydr. Def. (SCHAD)

Medium-Chain Acyl-CoA Dehydrogenase Def. (MCAD)

Trifunctional Protein Deficiency

Very Long-Chain Acyl-CoA Dehydrogenase Def. (VLCAD)

Long-Chain Acyl-CoA Dehydrogenase Def. (LCAD)

2,4 Dienoyl-CoA Reductase Deficiency



MS/MS - Organic Acidemias

Glutaric AciduriaType I (GA-1)

3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency (HMG)

Isobutyryl-CoA Dehydrogenase Deficiency

Isovaleric Acidemia (IVA)

Malonic Aciduria

3-Methylcrotonyl-CoA Carboxyl Deficiency (3-MCC)

Methylmalonic Acidemia (MMA)

Mitochondrial Acetoacetyl-CoAThiolase Def (3-

Ketothiolase) Propionic Acidemia (PA)

2-Methylbutyrl-CoA Dehydrogenase Deficiency

MultipleCoACarboxylase Deficiency



MS/MS- Amino Acidemias and Urea Cycle Disorders

Argininemia Argininosuccinate Lyase Deficiency (ASA)

Carbamoylphosphate Synthetase Deficiency(CPS)

Citrullinemia Hyperammonemia, Hyperornithinemia,

Homocitrullinuria (HHH)

Nonketotic hyperglycinemia

5-oxoprolinuria Tyrosinemia type I Tyrosinemia type II



Tandem Mass Spectrometry

if already in place, MS/MS alters criteria for

panel inclusion

prevalence not a consideration treatment not a consideration

cost not a consideration

requires large capital investment

requires uncommon technical and clinical

expertise



Screening tests across U.S.

Test panel is not uniform

Advocacy is for uniform panel

probably should be a federal program ensure high technical and clinical expertise

cost-effective LC-MS/MS is very expensive

Note that newborn screening is genetic

testing laws concerning dissent vary



Newborn screening

Success is testimony to:

basic science

medical science technology

public policy



Online Resources for Newborn Screening

NIHs Online Mendelian Inheritance in Man

(OMIM)

National Newborn Screening and GeneticsResourceCenter

State screening program websites

Public advocacy websites

MS/MS websites

16. neonatal screening

Documents