Population-Based Newborn Screening

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Phenylalanine

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Phenylalanine-->Tyrosine (by PAH)
Phenylalanine-->phenylpyruvic acid
phenylpyruvic acid--> phenyllactic acid
phenylpyruvic acid--> phenylacetic acid

80% of phe metabolized
Normal phe ~ 100 uM
PKU ~ 1500 uM
Phe--> brain --> neurotoxicity
Phe is essential AA

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PKU

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Phenylketonuria (PKU) is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH), rendering it nonfunctional.[1]:541 This enzyme is necessary to metabolize the amino acid phenylalanine (Phe) to the amino acid tyrosine. When PAH activity is reduced, phenylalanine accumulates and is converted into phenylpyruvate (also known as phenylketone), which can be detected in the urine.

Untreated --> developmental delay --> intellectual disability
Eczema
Autism
Light complexion (albinism)
Musty odor

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Treatment of PKU

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Dietary:
Phe-free AA mix
Low-protein foods

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Guthrie test

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The neonatal heel prick or Guthrie test is a screening test done on newborns. It consists of making a pinprick puncture in one heel of the newborn and soaking the blood into pre-printed collection cards known as Guthrie cards.

Bacterial assay
Growth zone

Front 5

Methionine

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Methionine --> Homocysteine -/-> Cystathionine

Homocystinuria

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Galactose

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Galactose --> Galactose-1-P -/-> Glucose-1-P

Galactosemia: results in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage, and ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.

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Leucine

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Leucine->alpha-ketocaproic acid -/-> Isovaleryl-CoA

Maple syrup urine disease (MSUD)

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Maple syrup urine disease (MSUD)

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Also called branched-chain ketoaciduria.
Neonatal disease
Mental retardation
Ketoacidosis
Maple syrup odor (ear)
Increased leucine

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Homocystinuria

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Mental retardation
Ectopia lentis
Skeletal abnormalities
Thromboembolism
Increase Methionine

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Congenital hypothyroidism

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Mental retardation
Coarse facies
Hypotonia
Growth delay
Reduced thyroxine

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Criteria for newborn screening

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Importance, feasibility, social impact.

Important health problem
accepted treatment
Facilities for Dx and Rx available
Latent or early symptoms
Suitable test
Test acceptable to population
Natural history understood
Agreement on whom to treat
Cost balanced re costs of medical care

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Glutaric acidemia I

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Macrocephaly
Encephalopathic episodes
Dysptonia

Lysine + Tyrptophan --> Glutaryl-CoA -/-> Glutaconyl-CoA (by Glutaryl-CoA dehydrogenase)
lead to
Glutaryl-CoA --> Glutaric Acid

Cause damage to the brain (and also other organs), but particularly the basal ganglia, which are regions that help regulate movement. GA1 causes secondary carnitine deficiency, as glutaric acid, like other organic acids, is detoxified by carnitine. Mental retardation may also occur.

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Carnitine

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A quaternary ammonium compound biosynthesized from the amino acids lysine and methionine.

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MCADD

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Medium-chain acyl-CoA dehydrogenase deficiency, often known as MCAD deficiency or MCADD is a disorder of fatty acid oxidation that impairs the body's ability to break down medium-chain fatty acids into acetyl-CoA. The disorder is characterized by hypoglycemia and sudden death without timely intervention, most often brought on by periods of fasting or vomiting. Prior to expanded newborn screening, MCADD was an underdiagnosed cause of sudden death in infants. Individuals who have been identified prior to the onset of symptoms have an excellent prognosis. It is most prevalent in individuals of Northern European Caucasian descent, with an incidence of 1:4000 to 1:17,000 depending on the population. Treatment of MCADD is mainly preventative, by avoiding fasting and other situations where the body relies on fatty acid oxidation to supply energy.

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Interpretation of metabolic testing

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PKU phe
MCADD C8
Propionic acidemia C3

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Propionic acidemia

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The disorder presents in the early neonatal period with progressive encephalopathy. Death can occur quickly, due to secondary hyperammonemia, infection, cardiomyopathy, or basal ganglial stroke.

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Krabbe disease

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A progressive degenerative disorder of the nervous system that involves the destruction of myelin, a fatty material that surrounds and insulates nerves. Most patients have the infantile form of Krabbe disease. During the first few months of life, they seem normal, but before 6 months of age, the signs of extreme irritability, spasticity, and developmental delay become evident. Neurological deterioration leads to death generally before age 2. Other forms of Krabbe disease have late infantile, juvenile, or adult age of onset. Krabbe disease is inherited in an autosomal recessive manner and is due to a mutation in the gene for galactosylceramidase (GALC), leading to the accumulation of galactocerebroside in tissues. Diagnosis is made by finding 5 percent or less of normal GALC activity. Prenatal diagnosis is feasible. Also known as galactocerebrosidase deficiency, GALC deficiency, and globoid cell leukodystrophy.

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New Areas of NBS

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Lysosomal storage disorders (LSD)
Krabbe
Severe combined immunodeficiency (SCID)
Wilson disease
Duchenne Muscular Dystrophy
Hereditary hemochromatosis

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Risk for Parkinsonism

Back 19

LRRK2 Gly2019Ser OR=3