Inborn errors of metabolism: Identifying the specific disorder
- V Reid Sutton, MD
V Reid Sutton, MD
- Professor of Molecular and Human Genetics
- Baylor College of Medicine
Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite (table 1 and table 2 and table 3 and table 4 and table 5 and table 6). Optimal outcome for children with inborn errors of metabolism (IEM) depends upon recognition of the signs and symptoms of metabolic disease, prompt evaluation, and referral to a center familiar with the evaluation and management of these disorders . Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death.
This topic provides an overview of the evaluation for children with suspected IEM. Confirmation of diagnosis of specific disorders typically requires specialized testing and should be undertaken in consultation with a specialist in genetics or metabolic diseases. The classification, most common presentations, and initial evaluation and management of IEM, particularly those that present as metabolic emergencies, are discussed separately, as are individual disorders. (See "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features" and "Inborn errors of metabolism: Metabolic emergencies".)
A newborn may present with a positive newborn screen for inborn errors of metabolism (IEM) before clinical manifestations are present or recognized. Newborn screening programs screen all newborns for a specific set of IEM . The testing methods and disorders that are screened vary from state to state and country to country. (See "Newborn screening".)
Newborn screening programs increase the detection of IEM, but cannot be relied upon exclusively. False-positive and false-negative screening tests occur, usually as a result of screening too early (ie, before adequate "challenge" with protein or carbohydrate), medications, and/or transfusions [3,4]. In addition, the results of the screening tests may not be available in the first few days of life, when some IEM may present. Furthermore, newborn screening programs do not screen for all IEM. As an example, the urea cycle disorders ornithine transcarbamylase deficiency and carbamylphosphate synthetase deficiency are not detected by available newborn screening methods. Improved detection depends upon a high index of suspicion. Guidelines for evaluation following an abnormal newborn screen can be found in ACTion (ACT) sheets from the American College of Medical Genetics. These guidelines and other helpful information are also often available from the state newborn screening program (including postings on their websites). (See "Newborn screening".)
The history should focus on previous episodes of metabolic decompensation, identification of potential triggering events, and family history of metabolic disease or members with similar presentations.
- Champion MP. An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed 2010; 95:40.
- Pasquali M, Longo N. Newborn screening and inborn errors of metabolism. Am J Med Genet C Semin Med Genet 2011; 157C:1.
- Couce ML, Castiñeiras DE, Bóveda MD, et al. Evaluation and long-term follow-up of infants with inborn errors of metabolism identified in an expanded screening programme. Mol Genet Metab 2011; 104:470.
- Clark RH, Kelleher AS, Chace DH, Spitzer AR. Gestational age and age at sampling influence metabolic profiles in premature infants. Pediatrics 2014; 134:e37.
- Leonard JV, Morris AA. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr 2006; 95:6.
- Wilcken B, Leung KC, Hammond J, et al. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 1993; 341:407.
- Mansouri A, Fromenty B, Durand F, et al. Assessment of the prevalence of genetic metabolic defects in acute fatty liver of pregnancy. J Hepatol 1996; 25:781.
- Walter JH. Inborn errors of metabolism and pregnancy. J Inherit Metab Dis 2000; 23:229.
- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102:E69.
- Lindor NM, Karnes PS. Initial assessment of infants and children with suspected inborn errors of metabolism. Mayo Clin Proc 1995; 70:987.
- Weiner DL. Metabolic emergencies. In: Textbook of pediatric emergency medicine, 5th ed, Fleisher GR, Ludwig S, Henretig FM (Eds), Lippincott, Williams and Wilkins, Philadelphia 2006. p.1193.
- Roth KS. Inborn errors of metabolism: the essentials of clinical diagnosis. Clin Pediatr (Phila) 1991; 30:183.
- Ramaswami U, Whybra C, Parini R, et al. Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey. Acta Paediatr 2006; 95:86.
- Banikazemi M, Ullman T, Desnick RJ. Gastrointestinal manifestations of Fabry disease: clinical response to enzyme replacement therapy. Mol Genet Metab 2005; 85:255.
- Calvo M, Artuch R, Macià E, et al. Diagnostic approach to inborn errors of metabolism in an emergency unit. Pediatr Emerg Care 2000; 16:405.
- Wappner RS, Hainline BE. Introduction to inborn errors of metabolism. In: Oski's pediatrics. Principles and practice, 4th ed, McMillan JA, Feigin RD, DeAngelis C, Jones MD (Eds), Lippincott, Williams & Wilkins, Philadelphia 2006. p.2145.
- Saudubray JM, Chappentier C. Clinical phenotypes: Diagnosis/algorithms. In: Metabolic and molecular bases of inherited disease, Scriver CR, Beaudet AL, Sly WS, Valle D (Eds), McGraw-Hill, New York 2001. p.1327.
- Cleary MA, Green A. Developmental delay: when to suspect and how to investigate for an inborn error of metabolism. Arch Dis Child 2005; 90:1128.
- Chakrapani A, Cleary MA, Wraith JE. Detection of inborn errors of metabolism in the newborn. Arch Dis Child Fetal Neonatal Ed 2001; 84:F205.
- Hansen L, Lind-Thomsen A, Joshi HJ, et al. A glycogene mutation map for discovery of diseases of glycosylation. Glycobiology 2015; 25:211.
- Taylor RW, Pyle A, Griffin H, et al. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 2014; 312:68.
- Tarailo-Graovac M, Shyr C, Ross CJ, et al. Exome Sequencing and the Management of Neurometabolic Disorders. N Engl J Med 2016; 374:2246.
- Yubero D, Brandi N, Ormazabal A, et al. Targeted Next Generation Sequencing in Patients with Inborn Errors of Metabolism. PLoS One 2016; 11:e0156359.
- Miller MJ, Kennedy AD, Eckhart AD, et al. Untargeted metabolomic analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis 2015; 38:1029.
- Atwal PS, Donti TR, Cardon AL, et al. Aromatic L-amino acid decarboxylase deficiency diagnosed by clinical metabolomic profiling of plasma. Mol Genet Metab 2015; 115:91.
- Treatable intellectual disability. An interactive tool for the clinician. http://www.treatable-id.org/.
- Ernst LM, Sondheimer N, Deardorff MA, et al. The value of the metabolic autopsy in the pediatric hospital setting. J Pediatr 2006; 148:779.
- Bennett MJ, Ragni MC, Hood I, Hale DE. Comparison of post-mortem urinary and vitreous humour organic acids. Ann Clin Biochem 1992; 29 ( Pt 5):541.
- NEWBORN SCREENING
- CLINICAL EVALUATION
- LABORATORY EVALUATION
- Initial evaluation
- Specialized tests
- - Plasma amino acids
- - Urine organic acids
- - Lactate and pyruvate
- - Acylcarnitine profile
- - Molecular genetic testing
- - Other
- EVALUATION OF SPECIFIC PRESENTATIONS
- Metabolic emergencies
- Developmental delay
- Skeletal myopathy
- SUMMARY AND RECOMMENDATIONS