Inborn errors of metabolism (IEMs) are singlegene disorders that block a normal metabolic process and produce a nonmetabolized substance that often has serious, in some cases fatal, consequences. Each of the over 300 known IEMs is of low prevalence in the population at large, ranging from 1/10,000 to perhaps 1/350,000 births, but in combination affect about 1 in every 2,500 to 5,000 births. Additionally, a few are far more prevalent in some groups than others. TaySachs, for example, although generally rare, occurs in about 1/3,500 Ashkenazi Jews. In most cases, effects do not begin until sometime after birth when the newborn begins to eat and metabolize its own food.
Most IEMs are autosomal recessive, and are manifested equally in males and females who have inherited a mutant recessive gene from each parent. A few, Lesch-Nyhan for example, are X-linked and manifested largely or solely in males.
Onset And Developmental Progression
IEMs may present at any time during life with a variety of symptoms and rate of progression, making some diagnoses difficult. Most affected individuals appear normal at birth, although some disorders have facial and other physical characteristics. Batshaw and Tuchman describe three types in terms of their first appearance: (1) Silent disorders (e.g., phenylketonuria and congenital hypothyroidism) are not apparent until severe developmental delay and mental retardation occur in infancy or childhood unless they have been identified in newborn testing. (2) Disorders (e.g., urea cycle disorder and organic acidemias) presenting, at about 3 days of age, acute metabolic crisis and severe symptoms, including vomiting, respiratory distress, abnormal odor, and lethargy followed by coma. These symptoms also characterize other newborn disorders, complicating diagnosis. Death generally follows in the absence of accurate diagnosis and acute medical intervention. (3) Disorders with progressive neurological deterioration (e.g., lycosomal storage disorders, including Tay-Sachs, Hurler, and metachromatic leukodystrophy) show apparently normal development for some period followed by loss of motor and cognitive skills, general nonresponsiveness, and death in infancy or early childhood.
Categorical systems are based on the type of metabolic error, but no one system has been adopted. The following is taken from Weiner with examples from various sources.
- Disorders of protein metabolism (e.g., amino acidopathies, including PKU and maple syrup urine syndrome)
- Disorders of carbohydrate metabolism (e.g., galactosemia)
- Lysosomal storage disorders (e.g., mucopolysaccharidoses [MPS], Tay-Sachs)
- Fatty acid oxidation defects (e.g., medium chain acyl-CoA dehydrogenase deficiency [MCAD])
- Mitochondrial disorders (e.g., mtDNA depletion syndromes)
- Peroxisomal disorders (e.g., Zellweger syndrome)
As Kelley suggests, pediatricians routinely see infants and young children with developmental delay or mental retardation, but no clear sign of an IEM.
Specific IEM diagnosis is generally through blood or urine test, but many can be identified prenatally through specific amniocentesis or chorionic villus sampling assay. Some signs in the newborn period, as indicated above, are highly suggestive of an IEM. According to Weiner, the following are potential signs of an IEM: any severe illness in a newborn; unexplained death of a sibling; otherwise undiagnosed developmental delay or motor and/or cognitive deterioration; onset of symptoms in reaction to change in diet or unusual dietary preferences; apparent toxic reactions to certain foods, particularly proteins or carbohydrates; and exaggerated symptoms from routine infections.
Several IEMs can be identified through routine neonatal screening. Although virtually all hospitals now screen for PKU, screening for other IEMs varies widely.
Treatment And Outcome
Several forms of treatment are effective in at least partially reducing the impact of a variety of IEMs, particularly those that can be identified in neonatal screening. Batshaw and Tuchman describe the following approaches: (1) limit intake of toxic substance through its elimination from the diet or a specially designed diet; (2) provide deficient enzyme to enable normal metabolism; (3) stimulate a detour around the metabolic block through medication; (4) provide a vitamin co-factor to increase deficient enzyme action; (5) provide synthetic enzyme replacement; (6) transplant a normal organ to supply needed enzyme; (7) employ gene therapy.
Outcome of treatment varies widely from prevention of most adverse effects of some IEMs (e.g., PKU and galactosemia) to those where no treatment is available and the disease’s progression is unavoidable. Overall, treatment for about half of known IEMs increases affected individuals’ longevity, growth, cognitive functioning, and other functions. In many cases, treatment will be lifelong.
- Batshaw, L., & Tuchman, M. (2003). PKU and other inborn errors of metabolism. In M. L. Batshaw (Ed.), Children with disabilities (5th ed., pp. 333–345). Baltimore: Brookes.
- Kelley, R. I. (1996). Metabolic diseases. In A. J. Capute & P. J. Accardo (Eds.), Developmental disabilities in infancy and childhood (2nd , pp. 113–136). Baltimore: Brookes.
- Weiner, L. (2001). Pediatrics, inborn errors of metabolism.
- In G. Wilkes, R. Konop, W. Wolfram, J. Halamka, & W. K. Mallon (Eds.), eMedicine world medical library. Retrieved from http://www.emedicine.com/emerg/topic768.htm