Inborn Errors of Metabolism

George E. Tiller

Inborn errors of metabolism are last on everyone’s list of differential diagnoses because of their individual rarity. They must always be considered in the evaluation of:

An acutely ill neonate or infant
Organomegaly
Failure to thrive
Mental retardation (MR)
Developmental delay (especially a regression)

All states screen newborns for phenylketonuria, hypothyroidism, congenital adrenal hyperplasia, and galactosemia because these conditions are treatable and screening methods are inexpensive. Many states are adopting expanded metabolic screening, often including many untreatable disorders. However, several disorders are still not currently detectable by newborn screening.

The main objectives of this chapter are to help the reader:

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

Selected disorders of inborn errors of metabolism are listed in Table 43.1.

PRINCIPLES OF NONSELECTIVE SCREENING OF NEWBORNS

Several important principles are critical in determining the disorders for which newborns should be screened for nonselectively. The disorder must be a heavy burden for the affected person to bear (i.e., be deadly, devastating). It should be preventable and treatable, with a known inheritance pattern and pathogenesis. The methods of screening, diagnosis, and management must be practical and available to the general population, and genetic counseling must also be available. Finally, the benefit-to-cost ratio of nonselective screening must be high, as must be its sensitivity and specificity (no false-negative results and a low rate of false-positive results).

Newborn screening programs consists of five processes: 1. Newborn testing 2. Follow-up of abnormal screening results to facilitate timely diagnostic testing and management 3. Diagnostic testing 4. Genetic counseling and disease management 5. Continuous evaluation and improvement of the newborn screening system (Kaye et al., 2006).

Some diseases for which newborns can be screened are listed in Table 43.2.

The pitfalls of newborn screening include technical problems (e.g., mishandling and mislabeling of the sample, generation of false-positive and -negative results) and poor communication among the laboratory, primary care provider, family, and subspecialist. With some disorders, optimal testing entails a dietary prerequisite, which can contribute to invalid sampling and necessitate repeating studies.

Features of selected diseases detectable by screening are summarized in the following.

Disorders of Amino Acid Metabolism

Phenylketonuria

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

Homocystinuria

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

DISORDERS OF CARBOHYDRATE METABOLISM

Galactosemia

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

CONGENITAL ADRENAL HYPERPLASIA

This is discussed in Chapter 16.

HYPOTHYROIDISM

This is discussed in Chapter 17.

DISORDERS OF FATTY ACID OXIDATION

Medium-Chain Acyl Coenzyme A Dehydrogenase (MCAD) Deficiency

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

DISORDERS OF BIOTIN METABOLISM

Biotinidase Deficiency

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 reactions

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