An acutely ill neonate or infant
Organomegaly
Failure to thrive
Mental retardation (MR)
Developmental delay (especially a regression)
Understand the basis, selectivity, and shortcomings of neonatal metabolic screening
Develop a general approach to the diagnosis of metabolic disease based on the use of readily available laboratory tests
Appreciate the often critical nature of inborn errors of metabolism, and the components of initial management
Become familiar with the features of a few representative inborn errors of metabolism
Incidence: 1 in 15,000 (most common amino acid disorder)
Screening test: Phenylalanine determination (dried blood spot)
TABLE 43.1 SELECTED EXAMPLES OF INBORN ERRORS OF METABOLISM
Amino Acidurias
Organic Acidurias
Urea Cycle Disorders
Phenylketonuria
Methylmalonic aciduria
Ornithine transcarbamylase deficiency (XLR)
Homocystinuria
Propionic aciduria
Arginosuccinate deficiency
Tyrosinemia
Maple syrup urine disease
Carbamyl phosphate synthetase deficiency
Nonketotic hyperglycinemia
Transport disorders
Peroxisomal disorders
Carbohydrate disorders
Cystinuria
Adrenoleukodystrophy (XLR)
Galactosemia
Cystinosis
Zellweger syndrome
Fructose intolerance
Hypercholesterolemia (AD)
Chondrodysplasia punctata
Glycogen storage diseases
Lysosomal disorders
Metal metabolic disorders
Lipidoses
Mucopolysaccharidoses
Wilson disease
Tay-Sachs disease
Hurler syndrome (MPS I)
Menkes disease (XLR)
Gaucher disease
Hunter syndrome (MPS II; XLR)
Hemochromatosis
Metachromatic leukodystrophy
I-cell disease (ML II)
Fatty acid oxidation defects
Purine metabolic disorders
Mitochondrial disorders
MCAD deficiency
Lesch-Nyhan syndrome (XLR)
Leber hereditary optic neuropathy (MI)
Disorders of steroid metabolism
MELAS (MI)
Smith-Lemli-Opitz syndrome
Congenital adrenal hyperplasia
Except for those disorders marked X-linked-recessive (XLR), autosomal dominant (AD), or mitochondrial (maternal) inheritance (MI), all the disorders listed in the table are inherited in an autosomal recessive pattern. MCAD, medium-chain acyl coenzyme A dehydrogenase; MELAS, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
TABLE 43.2 REPRESENTATIVE DISEASES FOR WHICH NEWBORNS CAN BE SCREENED
Disease
Incidence
Screening Test
Amino acid disorders
▪ Phenylketonuria
1/15,000
Phenylalanine
▪ Tyrosinemia
1/100,000
Tyrosine, succinylacetone
▪ Homocystinuria
1/100,000
Methionine
▪ Nonketotic hyperglycinemia
1/75,000
Glycine
▪ Maple syrup urine disease
1/100,000
Leucine, valine, isoleucine, alloisoleucine
Carbohydrate disorders
▪ Galactosemia
1/30,000
Galactose, gal-1-P transferase (GALT)
Organic acidemias
▪ Methylmalonic acidemia
1/100,000
C3, C4-DC
▪ Propionic acidemia
1/100,000
C3
▪ Isovaleric acidemia
1/100,000
C5
Fatty acid disorders
▪ SCAD
1/100,000
C4
▪ MCAD
1/15,000
C6-C10
▪ LCHAD
1/100,000
C14-OH, C16-OH
▪ LCAD
1/100,000
C14, C16, C18
▪ CPT deficiency
1/100,000
C16, C16:1,C18, C18:1
Other disorders
▪ Hypothyroidism
1/4500
T4, TSH
▪ Hemoglobinopathies (SS, SC, others)
1/400 US blacks
Hemoglobin electrophoresis
▪ Biotinidase deficiency
1/60,000
Biotinidase
▪ Congenital adrenal hyperplasia
1/10,000
17-Hydroxyprogesterone
▪ Cystic fibrosis
1/3200 whites
Immunoreactive trypsinogen
State screening programs vary in methodologies employed, and therefore differ in the number of disorders that can be detected.
C3, a 3-carbon carboxylic acid; C4-DC, a 4-carbon dicarboxylic acid; C14-OH, a 14-carbon hydroxy-fatty acid; C16:1, a 16-carbon mono-unsaturated fatty acid; CPT, carnitine palmitoyl transferase; LCHAD, long-chain 3-hydroxyacyl-coenzyme A dehydrogenase; MCAD, medium-chain acyl-coenzyme A dehydrogenase; SCAD, small-chain acyl-coenzyme A dehydrogenase; T4, thyroxine; TSH, thyroid-stimulating hormone; VLCAD, very long-chain acyl-coenzyme A dehydrogenase.
Prerequisite: Protein intake for longer than 24 hours
Diagnostic test: Quantitative phenylalanine determination (plasma amino acid profile)
Clinical features: Moderate to severe MR, autism, seizures, hypopigmentation, eczema
Primary defect: Phenylalanine hydroxylase deficiency
Treatment: Diet low in phenylalanine (low in protein; lifelong treatment optimal); tetrahydrobiopterin (BH4) supplementation in mild cases
Remarks: High phenylalanine levels and phenyl ketones are teratogenic. Untreated maternal phenylketonuria is associated with intrauterine growth retardation, microcephaly, MR, and structural birth defects
Incidence: 1 in 100,000
Screening test: Methionine determination (dried blood spot)
Prerequisite: Protein intake for longer than 24 hours
Diagnostic test: Measurement of methionine and homocystine levels in plasma (sent to laboratory on ice for amino acid profile)
Clinical features: Tall stature, scoliosis, osteoporosis, mild MR, ectopia lentis, hypercoagulability, arterial and venous thrombi, stroke
Primary defect: Cystathionine beta-synthetase deficiency (most common type)
Treatment: Supplementation with betaine, folate, pyridoxine, or all three, depending on defect; aspirin for anticoagulation
Incidence: 1 in 30,000
Screening test: Galactose, galactose-1-phosphate uridyltransferase (GALT) determination
Prerequisite: Galactose (lactose) intake
Diagnostic test: GALT electrophoresis
Clinical features: Neonatal nausea and vomiting, jaundice, hepatomegaly, hepatic dysfunction, cataracts, MR, death
Primary defect: GALT deficiency
Treatment: Galactose-free, lactose-free diet
Incidence: 1 in 15,000
Screening test: Acylcarnitine profile (plasma or dried blood spot)
Diagnostic test: Repeated plasma acylcarnitine profile, DNA mutation testing
Clinical features: Hypoglycemia without ketonuria; at risk for coma, sudden infant death syndrome
Primary defect: MCAD deficiency
Treatment: Carnitine supplementation; frequent feedings, avoid hypoglycemia
Incidence: 1 in 60,000
Screening test: Enzyme assay from dried blood spot; increased plasma alanine, decreased carnitine also seen
Diagnostic test: Repeat enzyme assay on fresh serum
Clinical features: Hypotonia, seizures, rashes, alopecia
Primary defect: Biotinidase deficiency, an enzyme that recycles biotin for multiple carboxylase enzyme reactionsStay updated, free articles. Join our Telegram channel
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