Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features
- 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). Most of these disorders are transmitted as autosomal recessive traits.
The possibility of an inborn error of metabolism (IEM) should be considered in infants, children, and adults who present with any of the clinical or laboratory features discussed below or in the topic review on metabolic emergencies, particularly if the findings remain unexplained after standard evaluation [1-6]. (See "Inborn errors of metabolism: Metabolic emergencies" and 'Age at presentation' below.)
Optimal outcome for children with IEM depends upon recognition of the signs and symptoms of metabolic disease and prompt evaluation and referral to a center familiar with the management of these disorders . Delay in diagnosis may result in acute metabolic decompensation, progressive neurologic injury, or death.
The epidemiology, pathogenesis, and most common chronic clinical and laboratory manifestations of IEM are discussed below. The presentation, initial diagnosis, and management of IEM presenting as metabolic emergencies are discussed in detail separately. The major classes of IEM and their characteristic clinical and biochemical features are described elsewhere, as is a diagnostic approach to identifying the specific IEM. In addition, many of the individual disorders are covered in separate topic reviews (see specific topic reviews). (See "Inborn errors of metabolism: Metabolic emergencies" and "Inborn errors of metabolism: Classification" and "Inborn errors of metabolism: Identifying the specific disorder".)
Individual inborn errors of metabolism (IEM) are rare disorders, most having an incidence of less than 1 per 100,000 births. However, when considered collectively, the incidence may approach 1 in 800 to 1 in 2500 births [8,9]. In one review of cases of IEM diagnosed in British Columbia (a predominantly Caucasian population) between 1969 and 1996, estimates of incidence of various classes of disorders were as follows:
- 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.
- Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: A retrospective analysis. J Pediatr 1999; 134:268.
- 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.
- Leonard JV, Morris AA. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth. Acta Paediatr 2006; 95:6.
- Lindor NM, Karnes PS. Initial assessment of infants and children with suspected inborn errors of metabolism. Mayo Clin Proc 1995; 70:987.
- Wappner RS. Biochemical diagnosis of genetic diseases. Pediatr Ann 1993; 22:282.
- Champion MP. An approach to the diagnosis of inherited metabolic disease. Arch Dis Child Educ Pract Ed 2010; 95:40.
- Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics 2000; 105:e10.
- Sanderson S, Green A, Preece MA, Burton H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch Dis Child 2006; 91:896.
- 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.
- Curry CJ, Stevenson RE, Aughton D, et al. Evaluation of mental retardation: recommendations of a Consensus Conference: American College of Medical Genetics. Am J Med Genet 1997; 72:468.
- Powell K, Van Naarden Braun K, Singh R, et al. Prevalence of developmental disabilities and receipt of special education services among children with an inborn error of metabolism. J Pediatr 2010; 156:420.
- Treatable intellectual disability. An interactive tool for the clinician. http://www.treatable-id.org/.
- De Vivo DC, DiMauro S. Hereditary and acquired types of myopathy. In: Oski's pediatrics. Principles and practice, 3rd ed, McMillan JA, DeAngelis CD, Feigin RD, Warshaw JB (Eds), Lippincott, Williams and Wilkins, Philadelphia 1999. p.1971.
- Scheuerle AE, McVie R, Beaudet AL, Shapira SK. Arginase deficiency presenting as cerebral palsy. Pediatrics 1993; 91:995.
- 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 and Wilkins, Philadelphia 2006. p.2145.
- Zhang B, Porto AF. Cholesteryl ester storage disease: protean presentations of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr 2013; 56:682.
- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998; 102:E69.
- Cormier-Daire V, Rustin P, Rötig A, et al. Craniofacial anomalies and malformations in respiratory chain deficiency. Am J Med Genet 1996; 66:457.
- von Kleist-Retzow JC, Cormier-Daire V, Viot G, et al. Antenatal manifestations of mitochondrial respiratory chain deficiency. J Pediatr 2003; 143:208.
- Poll-The BT, Maillette de Buy Wenniger-Prick CJ. The eye in metabolic diseases: clues to diagnosis. Eur J Paediatr Neurol 2011; 15:197.
- Demitsu T, Kakurai M, Okubo Y, et al. Skin eruption as the presenting sign of Hunter syndrome IIB. Clin Exp Dermatol 1999; 24:179.
- Prystowsky SD, Maumenee IH, Freeman RG, et al. A cutaneous marker in the Hunter syndrome a report of four cases. Arch Dermatol 1977; 113:602.
- Hackbart BA, Arita JH, Pinho RS, et al. Mongolian spots are not always a benign sign. J Pediatr 2013; 162:1070.
- Van Maldergem L, Jauniaux E, Fourneau C, Gillerot Y. Genetic causes of hydrops fetalis. Pediatrics 1992; 89:81.
- Stone DL, Sidransky E. Hydrops fetalis: lysosomal storage disorders in extremis. Adv Pediatr 1999; 46:409.
- Kattner E, Schäfer A, Harzer K. Hydrops fetalis: manifestation in lysosomal storage diseases including Farber disease. Eur J Pediatr 1997; 156:292.
- Wisser J, Schreiner M, Diem H, Roithmeier A. Neonatal hemochromatosis: a rare cause of nonimmune hydrops fetalis and fetal anemia. Fetal Diagn Ther 1993; 8:273.
- Fayon M, Lamireau T, Bioulac-Sage P, et al. Fatal neonatal liver failure and mitochondrial cytopathy: an observation with antenatal ascites. Gastroenterology 1992; 103:1332.
- de Koning TJ, Toet M, Dorland L, et al. Recurrent nonimmune hydrops fetalis associated with carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 1998; 21:681.
- Alegria A, Martins E, Dias M, et al. Glycogen storage disease type IV presenting as hydrops fetalis. J Inherit Metab Dis 1999; 22:330.
- Mace JW, Goodman SI, Centerwall WR, Chinnock RF. The child with an unusual odor. A clinical resumé. Clin Pediatr (Phila) 1976; 15:57.
- Ahrens-Nicklas RC, Slap G, Ficicioglu C. Adolescent presentations of inborn errors of metabolism. J Adolesc Health 2015; 56:477.
- CLINICAL MANIFESTATIONS
- - Lethargy, coma, and seizures
- - Developmental delay
- - Neuropathy
- - Abnormal tone
- - Myopathy
- - Ataxia and dystonia
- - Neuropsychiatric
- - Vomiting and poor feeding
- - Organomegaly
- - Jaundice
- Dysmorphic features
- Hydrops fetalis
- Abnormal odors
- Urine changes
- AGE AT PRESENTATION
- LABORATORY FINDINGS
- Acid-base disorders, hyperammonemia, and hypoglycemia
- Hematologic abnormalities
- Liver abnormalities
- Renal disease