Newborn Screening

Question 1

Newborn Screening General Principles

Answer 1

1) the target disease must be common enough and have severe enough symptoms to warrant testing many normal newborns to identify a few that are affected
2) an intervention must exist to prevent complications of the condition
3) there should be a cost-effective, sensitive and specific test that provides results quickly.

Question 2

Key Points to Discuss with Parents

Answer 2

1. Every baby is at risk and you can’t tell if a baby has a disorder without screening

Newborn screening is important for all babies because even without a family history of any of the screened disorders, every baby is at risk. Most babies with a disorder are born into a family with no other affected family members. Most affected babies look healthy at birth.

2. Disorders are serious and can be life-threatening

The screened disorders are serious and can cause severe disability or even death if not detected and treated early. For some disorders, symptoms appear quickly and for others the baby appears fine for a while before symptoms appear and by that time permanent damage has been done. Newborn screening is not just a PKU test anymore but includes hearing screening and a panel of 28 disorders detected by bloodspot testing.

3. How the testing will be done

A few large drops of blood are obtained by pricking the baby’s heel. These blood drops are collected on a special filter paper kit, dried, and sent to the State Lab for analysis. Hearing screening is done when the baby is quiet or asleep by a trained screener using equipment that provides an automated pass or refer result – sound is introduced into the baby’s ear and either an otoacoustic emission is measured or an auditory brainstem response is measured from scalp electrodes. This testing is painless and takes only a few minutes to complete.

4. Testing must be timely

The first bloodspot test should be done between 24 and 36 hours of age or prior to discharge from the hospital. For some disorders, false negative results can occur with later testing. The second screen should be done at the first outpatient visit to the medical home or other healthcare professional or between 5 and 10 days of age, whichever comes first. The hearing test will be done before the baby is discharged from the hospital. Any rescreening should be done within two weeks and diagnostic testing should be done as soon as possible following a failed outpatient screen. Completing diagnostic testing before three months of age ensures that testing can be done without sedation or anesthesia and that early intervention and fitting of hearing aids, if appropriate, can take place before six months of age. Babies that are in the neonatal intensive care unit for more than five days should go directly to a diagnostic evaluation if they fail the inpatient screen.

Question 3

Amino Acid Disorders

Answer 3

• PKU
• MSUD
• Homocystinuria (HCY)
• Citrullinemia Type I (CIT-1)
• Argininosuccinic Acidemia (ASA)
• Tyrosinemia Type 1 (TYR-1)

Question 4

Fatty Acid Oxidation Disorders

Answer 4

• Carnitine uptake defect (CUD)
• Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
• Very long-chain acyl-CoA dehydrogenase deficiency (VLCAD)
• Long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD)
• Trifunctional protein deficiency (TFP)

Question 5

Organic Acid Disorders

Answer 5

• Isovaleric acidemia (IVA)
• Glutaric acidemia type I (GA-1)
• 3-Hydroxy-3-methylglutaric aciduria (HMG)
• Multiple carboxylase deficiency (MCD)
• Methylmalonic acidemia-cobalamin defect (Cbl A,B)
• Methylmalonic acidemia-mutase deficiency (MUT)
• 3-Methylcrotonyl-CoA carboxylase deficiency (3MCC)
• Propionic acidemia (PROP)
• Beta-ketothiolase deficiency (BKT)

Question 6

Endocrine Disorders

Answer 6

• Congenital hypothyroidism (CH)
• Congenital adrenal hyperplasia (CAH)

Question 7

Hemoglobin Disorders

Answer 7

• Sickle cell anemia (Hb SS) S,
• beta-thalassemia (Hb S/ß Th)
• S, C disease (Hb S/C)

Question 8

Other Disorders

Answer 8

• Biotinidase deficiency (BIOT)
• Galactosemia (GALT)
• Cystic Fibrosis (CF)
• Severe Combined Immunodeficiency (SCID)

Question 9

Disorders not detected by bloodspot screening

Answer 9

• Hearing Loss (HEAR)
• Critical Congenital Heart Defects (CCHD)

Question 10

Phenylketonuria

Answer 10

•absence of phenylalanine hydroxylase activity

A musty odor in the breath, skin or urine, caused by too much phenylalanine in the body

Neurological problems that may include seizures

Skin rashes (eczema)

Fair skin and blue eyes, because phenylalanine can’t transform into melanin — the pigment responsible for hair and skin tone

Abnormally small head (microcephaly)

Hyperactivity

Intellectual disability

Delayed development

Behavioral, emotional and social problems

Psychiatric disorders

Question 11

Maple Syrup Urine Disease

Answer 11

• Defect in leucine, isoleucine and valine (the 3 branchedchain amino acids) metabolism that is life-threatening and causes severe neurologic damage if untreated
• more common in the Pennsylvania Old Order Mennonite;

poor feeding

vomiting

lack of energy (lethargy)

abnormal movements

delayed development

Question 12

FAOD - MCAD

Answer 12

• Unable to make energy when fasting
• Can present with sudden hypoglycemia
• Can be fatal
• Usually presents after a period of decreased food intake
• Infections
• Dieting

•Most common is MCAD

• Variety of others that can present with liver and cardiac disease
• VLCAD, LCHAD, TFP, CUD
• Treatment: avoid hypoglycemia
• Diagnosis: MS/MS detection of oxidated fatty acids

Question 13

Organic Acid Disorders - Methylmalonic Acidemia

Answer 13

• Organic acid disorders have symptoms including recurrent acidosis, hypoglycemia, and a variety of other signs and symptoms specific to the individual disorder.
• OADs that can be detected by newborn screening include:
• Methylmalonic aciduria, also known as methylmalonic acidemia, is an autosomal recessive condition that occurs when the enzyme, methylmalonyl-CoA mutase, necessary to break down certain lipids, amino acids and cholesterol is missing or not working properly.
• Symptoms start in the first days of life and include lethargy, dehydration, vomiting, hypotonia, respiratory depression, seizures and metabolic ketoacidosis which can lead to coma and death.
• Treatment includes avoiding fasting, antibiotics to suppress gut flora, B12 supplementation, and a low protein diet to prevent metabolic crises. Risk of this disorder is detected with elevated C3 by MS/MS.
• A later-onset version of the condition is caused by mutations in the cobalamin gene mutation.

Question 14

Hemoglobinopathies - SCD

Answer 14

• The hemoglobinopathies are a group of genetic disorders due to mutations in hemoglobin. There are hundreds of these disorders, and they have a variety of interesting clinical presentations depending on the effect the mutation has on hemoglobin function. Thus, we have sickle cell anemia, HbC, HbE, thalassemias, methemoglobinemias, polycythemias, etc. For newborn screening purposes, the target hemoglobinopathy is sickle cell disease.
• The major reason for screening for sickle cell disease is prevention of sepsis by using penicillin prophylaxis.
• The newborn screen will also identify a number of other hemoglobinopathies, including those with hemoglobin traits (heterozygotes). These patients are referred to a hematologist for further counseling and care.

Question 15

Biotinidase Deficiency

Answer 15

•patients develop signs and symptoms of biotin deficiency: alopecia (hair loss), seborrhea (a skin abnormality), seizures, hearing impairment, and developmental delay. Without a proper diagnosis, infants may be left neurologically damaged.

Question 16

Galactosemia Deficiency

Answer 16

•Patients with galactosemia present with liver toxicity in the first two weeks of life; they are often jaundiced and ill-appearing, and laboratory analysis reveals elevated transaminases (ALT and AST). The elevated blood galactose is filtered into the urine where it can be detected as a reducing substance. An elevation of urine reducing substances in conjunction with the typical symptoms, strongly suggests galactosemia. Restricting dietary intake of lactose treats affected infants. This is initially accomplished by switching the infant’s formula to a lactose-free formula (there are many but a common choice is Isomil). The symptoms of intoxication rapidly reverse, and the infants do very well on a lactose-free diet.

Question 17

Congenital Hypothyroidism

Answer 17

•Thyroid hormone is important for proper neurologic development, and infants with untreated hypothyroidism will become severely mentally retarded (cretinism). Other signs will include short stature, low muscle tone, difficulty feeding and constipation. Identification of infants with congenital hypothyroidism enables treatment with exogenous thyroid hormone replacement. This prevents the development of cretinism. Patients must be medically monitored to assure that the dosage of the thyroid hormone remains correct.

Question 18

Congenital adrenal hyperplasia (21-hydroxylase deficiency)

Answer 18

•Congenital adrenal hyperplasia is a collective clinical term used for genetic disorders of adrenal gland steroid synthesis. However, from a newborn screening standpoint, it refers to deficient activity of 21-hydroxylase, an important enzyme in cortisol synthesis. You have already had a CBI on this in the DMH block, so I will not repeat that information in this lecture. Key features include ambiguous genitalia. The major risk is of salt wasting crisis.

Question 19

Cystic Fibrosis

Answer 19

•CF presents with major damage to the pancreas, respiratory and reproductive systems. Children with CF may have thickened meconium, the first stool of an infant, that does not pass and causes ileus. Later in childhood, children with CF has problems with recurrent respiratory infections. Most males with CF have congenital bilateral absence of the vas deferens and are thus sterile. From a newborn screening standpoint, damage to the pancreas due to mucous “clogging” starts in utero. As the pancreatic acinar cells are damaged, they release trypsinogen into the blood stream. This elevation can be detected in the newborn screen blood spot. However, there are many false positives. Since 75% of CF is due to the ∆F508 mutation, many screening programs couple trypsinogen testing with DNA analysis for known CF mutations. The rationales for screening for CF are: 1) improvement of nutrition and growth and 2) genetic counseling of at risk families.

Question 20

SCID

Answer 20

•Severe Combined Immunodeficiency (SCID) includes a group of rare but serious and potentially fatal, inherited immune disorders in which T lymphocytes fail to develop and B lymphocytes are either absent or compromised. Impairment of both B and T cells leads to the term “combined.” Untreated patients develop life-threatening, infections due to bacteria, viruses and fungi. The screening test for T cell receptor excision circles (TRECs), a byproduct of normal T cell development, identifies SCID as well as certain related conditions with low T cells. For example, DiGeorge Syndrome with impaired thymus development may cause low T cells and low TRECs. X-linked SCID is the most common form, but an autosomal recessive form of SCID is frequent in some Native American communities. Treatment includes prophylactic infection prevention with stem cell transplantation within a few months of birth.

Question 21

Critical congenital heart defects

Answer 21

Critical congenital heart disease (CCHD) is a subset of congenital heart disease (CHD), comprising about 25% of CHD cases. Screening is done by checking pulse oximetry of the infant between 24- and 48-hours after birth. Testing is done in the right hand and one of the feet and the infant fails if any reading is 3% difference between right hand and foot. CCHD includes common truncus arteriosus, hypoplastic left heart syndrome, pulmonary valvular atresia, Tetralogy of Fallot, total anomalous pulmonary venous return, transposition of the great vessels, and tricuspid valvular atresia. These are ductus dependent malformations in which the children appear well but when the ductus closes the patient can deteriorate rapidly. There are other types of CCHD (such as coarctation of the aorta) that, although less likely to cause arterial desaturation, may be detected by physical examination and/or pulse oximetry. CCHD may be associated with decreased levels of oxygen in the arterial blood (hypoxemia) and may bring a significant risk of morbidity and mortality if not diagnosed soon after birth.

Question 22

Hearing Loss

Answer 22

More than 30 of 10,000 infants have hearing loss. Early detection of this can support the development of communication, language and social skills. Screening is done prior to 1 month of age, and then repeated by 3 months of age if the child fails the initial screen. Testing is done using Automated Auditory Brainstem Response (AABR) evaluation that measures whether brain signaling changes after a sound is played in the infant’s ear.