Newborn Screening Test Flashcards
What is ‘screening’?
Screening is a process of identifying apparently healthy people who may be at increased risk of a disease or condition. They can then be offered information, further tests and/or treatment to reduce their risk and/or complications.
What is Wilson and Jungner Criteria? What are the 5 main criteria?
Essential screening criteria:
- Disease must be sufficiently common
- Natural history must be known; the progression of a disease process in an individual over time, in the absence of treatment
- Early therapeutic intervention beneficial
- Acceptable and affordable screening test
- Diagnostic confirmatory test
When are all babies tested?
At 5 days
What details are found on the neonatal screening card?
NHS number, name, address, DOB, GP, mother’s details
DOB, DOS, gestation, weight, transfusion status, hospital status, repeat status
What does neonatal screening test for?
9 conditions:
- Sickle cell disease and Hb disorders
- Cystic fibrosis
- Congenital hypothyroidism
- Phenylketonuria (PKU)
- Maple syrup urine disease (MSUD)
- Isovaleric acidaemia (IVA)
- Glutaric aciduria type 1 (GA1)
- Homocystinuria (pyridoxine unresponsive) (HCU)
- Medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
How many people does PKU affect? What type of inheritance is it?
1:10,000 Caucasian births
Inherited in an autosomal recessive pattern
What is PKU? What is it caused by?
An inborn error of metabolism that results in decreased metabolism of phenylalanine, causing its build up.
Caused by a defect in the PAH gene
What can PKU result in?
Untreated, PKU can lead to intellectual disability, seizures, behavioural problems, and mental disorders. It may also result in a musty smell and lighter skin.
What is the prognosis of PKU?
Excellent if treated from birth
How can PKU be confirmed?
- Screening test
2. Confirm diagnosis with plasma phenylalanine measurements (no need to measure enzyme or DNA)
Case 1:
Female infant referred at 14 months to Community Paediatrics; parental concern with developmental delay
On examination:
- Sitting with support, not vocalising, or reaching out or picking up objects
- Not startled by noise
- Not recognising parents
- Parents reported 3 brief episodes of shaking and eye rolling
- No dysmorphism
- Normal pregnancy and birth in Algeria
- Parents first cousins
What is the prognosis?
Eventual IQ outcome correlates with blood Phe.
Pathophysiological determinant likely to be brain Phe.
- Uncertain, but unlikely to be very good
- Compliance has been good despite late start with diet
- Neurological damage not reversible
What is the treatment for PKU?
A low phenylalanine diet
Biopterin supplementation
Large neutral amino acids
What is the treatment for PKU?
A low phenylalanine diet
Biopterin supplementation (in the form sapropterin)
Large neutral amino acids supplementation (Val, Leu, Ileu)
What does a low phenylalanine diet involve?
A low-protein diet that completely avoids high-protein foods (such as meat, eggs and dairy products) and controls the intake of many other foods, such as potatoes and cereals.
People with PKU must also avoid food products that contain aspartame, as it’s converted into phenylalanine in the body.
How can a low phenylalanine diet lead to a tyrosine insufficiency?
High protein foods are also high in tyrosine and phenylalanine
What is the PAH gene needed for?
The PAH gene helps create phenylalanine hydroxylase, the enzyme responsible for breaking down phenylalanine.
What is the cofactor for phenylalanine hydroxylase?
Biopterin
How many people does congenital hypothyroidism affect?
1:1500 UK births
What is the prognosis for congenital hypothyroidism?
Severe developmental delay if untreated. Excellent prognosis if treated from birth
How is congenital hypothyroidism diagnosed?
Screening test: bloodspot TSH
Confirm diagnosis with plasma thyroid function tests
no need to measure enzyme or DNA
What is congenital hypothyroidism?
A disorder affecting the thyroid gland. The thyroid gland produces a hormone called thyroxine, which is needed for normal growth and development. If the thyroid gland does not produce enough thyroxine, it causes hypothyroidism.
How is congenital hypothyroidism caused?
- A missing, poorly formed, or abnormally small thyroid gland.
- A genetic defect that affects thyroid hormone production.
- Too little iodine in the mother’s diet during pregnancy.
- Radioactive iodine or antithyroid treatment for thyroid cancer during pregnancy.
What is the treatment for congenital hypothyroidism?
Treatment with thyroxine: carefully monitored
What is MCADD? How is it inherited?
Medium Chain Acyl CoA Dehydrogenase Deficiency
Autosomal recessive inherited defect of fatty acid oxidation.
Body cannot use its own fat reserves to produce energy in periods of fasting or metabolic stress.
How many people does MCADD affect?
1 : 10,000 UK births
During MCADD, the body cannot use its own fat reserves to produce energy in periods of fasting or metabolic stress. What does this lead to?
Hypoglycaemia and metabolic decompensation develop, which may result in seizures, brain damage or death
How is MCADD diagnosed?
Screening test: bloodspot C8 and C8/C10 ratio
Confirmation of diagnosis:
Bloodspot acylcarnitines, urine organic acids, DNA analysis
How is MCADD treated?
Avoidance of fasting
Prognosis for MCADD?
Good if decompensation avoided. ‘Safe’ times between meals increases as children grow older.
How many people does CF affect?
1 : 2500
Which is the most controversial that is screened for in neonates? Why?
Cystic fibrosis:
- Not all cases detected by IRT-DNA protocol
- Doubts about clinical benefits of early treatment
- Identification of less severe variants
- Identification of heterozygotes
What are Haemoglobinopathies? How are they inherited?
A group of recessively inherited genetic conditions affecting the haemoglobin component of blood.
They are caused by a genetic change (mutation) in the haemoglobin.
What is sickle cell disease caused by?
Caused by a mutation in the Hb-Beta gene found on chromosome 11.
In people with sickle cell disease, abnormal Hb molecules - HbS - stick to one another and form long, rod-like structures. These structures cause red blood cells to become stiff, assuming a sickle shape. Their shape causes these red blood cells to pile up, causing blockages and damaging vital organs and tissue. Also block the flow of blood through vessels.
How is sickle cell disease inherited?
Autosomal recessive pattern
What is beta thalassaemia?
An inherited blood disorder in which the body doesn’t make hemoglobin normally
Difference between beta thalassaemia and sickle cell disease?
While beta thalassemia is caused by a defect in the beta-globin gene, controlling the production of the beta-globin chains of hemoglobin, sickle cell disease is caused by a defect in hemoglobin itself with the presence of abnormal hemoglobin S.
What are the benefits of sickle cell disease screening?
20% children with undiagnosed SCD may die during first 2 years of life
- Acute infection
- Acute splenic sequestration
- Cerebrovascular accident – stroke
Screening provides improved outcomes
- Initiate prophylactic penicillin
- Parental education
What was the Expanded Screening Project?
Main aim: to assess false positive rates in our population
6 laboratories covering 50% English births (diversity of ethnicity )
Disorders: (overall incidence est at 1:28,000)
- Homocystinuria
- Maple syrup urine disease
- Glutaric aciduria type 1
- Isovaleric acidaemia
- LCHADD
What is Maple Syrup Urine Disease (MSUD)?
Defect in branched chain 2-keto acid dehydrogenase complex that is required to break down the 3 branched-chain amino acids (BCAAs) in the body; Valine, Isoleucine and Leucine.
The result of this metabolic failure is that all 3 BCAAs, along with their toxic byproducts, accumulate abnormally.
How is MSUD inherited?
Autosomal recessive
What are the clinical effects of MSUD?
The majority (75-80%) have the classical disease, presenting during the neonatal period, encephalopathy and cerebral oedema plus poor feeding, ketoacidosis and seizures
What is the screening target for MSUD?
Leucine
What is homocystinuria?
The body cannot metabolise methionine due to a deficiency of b-cystathionine beta synthase or methionine synthase.
How is homocystinuria inherited?
Autosomal recessive
How can homocystinuria be treated?
- pyridoxine responsive forms –> In some babies, it’s possible to control the levels of homocysteine with high doses of vitamin B6
- pyridoxine non-responsive forms –> referred to a specialist metabolic dietitian and given a low-protein diet
What is pyridoxine?
Vitamin B6
What are the clinical effects of homocystinuria?
Usually healthy at birth, the diagnosis is not usually made until the first 2-3 years of life. Myopia followed by dislocation of the lens, osteoporosis, thinning and lengthening of the long bones, mental retardation and thromboembolism.
Without treatment, 25% of patients will die before the age of 30, usually due to thromboembolism.
What is the screening target for homocystinuria?
Screening Target: methionine
Secondary target: total homocysteine
What is Glutaric aciduria Type 1? How is it inherited?
A deficiency of glutaryl-CoA dehydrogenase that is involved in the lysine metabolism
Autosomal recessive inheritance
What are the clinical effect of glutaric aciduria type 1?
About 70% of patients have an encephalopathic crisis, most commonly at around 9 months, with 90% by age 2 years precipitated by a non-specific intercurrent illness, gastrointestinal infection or pneumonia. Leads to dystonia and dyskinesia as permanent sequelae.
Of symptomatically diagnosed patients about 50% die before the age of 25 years. Survivors usually have severe handicap.
What is the screening target of glutaric aciduria type 1?
glutaryl carnitine (C5DC)
What is isovaleric acidaemia?
A deficiency of isovaleryl-CoA dehydrogenase involved in leucine catabolism.
What are the clinical effects of isovaleric acidaemia?
Spectrum of clinical phenotypes:
- acute neonatal presentations in the first two weeks of life. Infants are initially well, then develop vomiting and lethargy, progressing to coma.
- acute presentations at a later age, usually precipitated by an infection.
- chronic intermittent presentations, failure to thrive and/or developmental delay, usually within the first year.
What is the screening target in isovaleric acidaemia?
isovaleryl carnitine (C5)
What other conditions may newborns occasionally be screened for?
- Galactosaemia (via PKU pathway)
- Tyrosinaemia (via PKU pathway)
- GA2 (raised acylcarnitines)
What is the function of Acyl-CoA dehydrogenases (ACADs)?
A class of enzymes that function to catalyse the initial step in each cycle of fatty acid oxidation in the mitochondria of cells.
In which disease that is screened for in newborns;
a) can be treated with pyridoxine?
b) is controversial to screen for?
c) is caused by defect in PAH gene?
d) causes increased levels of lysine?
e) causes increased levels of leucine?
f) causes hypoglycaemia?
a) homocystinuria
b) CF
c) PKU
d) glutaric aciduria type 1
e) MSUD and isovaleric acidaemia
f) MCADD
Which 2 enzymes can be faulty in homocystinuria?
1) methionine synthase
2) Cystathionine-β-synthase
