Inborn Errors of Metabolism



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

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Jun 29, 2016 | Posted by in PEDIATRICS | Comments Off on Inborn Errors of Metabolism

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