Inborn errors of metabolism

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Gaucher disease-Pathological macrophages in bone marrow

Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities.[1] The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or due to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic disorders.[2] To this concept it's possible to include the new term of Enzymopathy. This term was created following the study of Biodynamic Enzymology, a science based on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism were studied for the first time by British physician Archibald Garrod (1857–1936), in 1908. He is known for work that prefigured the "one gene-one enzyme" hypothesis, based on his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism, was published in 1923.[3]


Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases.[4] In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class.[5]

Signs and symptoms

Because of the enormous number of these diseases the wide range of systems affected badly, nearly every "presenting complaint" to a healthcare provider may have a congenital metabolic disease as a possible cause, especially in childhood and adolescence. The following are examples of potential manifestations affecting each of the major organ systems.


Dozens of congenital metabolic diseases are now detectable by newborn screening tests, especially expanded testing using mass spectrometry.[6] Gas chromatography–mass spectrometry-based technology with an integrated analytics system has now made it possible to test a newborn for over 100 mm genetic metabolic disorders. Because of the multiplicity of conditions, many different diagnostic tests are used for screening. An abnormal result is often followed by a subsequent "definitive test" to confirm the suspected diagnosis.

Gas chromatography–mass spectrometry (GCMS)

Common screening tests used in the last sixty years:

Specific diagnostic tests (or focused screening for a small set of disorders):

A 2015 review reported that even with all these diagnostic tests, there are cases when "biochemical testing, gene sequencing, and enzymatic testing can neither confirm nor rule out an IEM, resulting in the need to rely on the patient's clinical course".[7] A 2021 review showed that several neurometabolic disorders converge on common neurochemical mechanisms that interfere with biological mechanisms also considered central in ADHD pathophysiology and treatment. This highlights the importance of close collaboration between health services to avoid clinical overshadowing.[8]


In the middle of the 20th century the principal treatment for some of the amino acid disorders was restriction of dietary protein and all other care was simply management of complications. In the past twenty years, new medications, enzyme replacement, gene therapy, and organ transplantation have become available and beneficial for many previously untreatable disorders. Some of the more common or promising therapies are listed:


In a study in British Columbia, the overall incidence of the inborn errors of metabolism were estimated to be 40 per 100,000 live births or 1 in 2,500 births,[9] overall representing more than approximately 15% of single gene disorders in the population.[9] While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.[10]

Type of inborn error Incidence
Disease involving amino acids (e.g. PKU, Tyrosinemia), organic acids,
primary lactic acidosis, galactosemia, or a urea cycle disease
24 per 100 000 births[9] 1 in 4,200[9]
Lysosomal storage disease 8 per 100 000 births[9] 1 in 12,500[9]
Peroxisomal disorder ~3 to 4 per 100 000 of births[9] ~1 in 30,000[9]
Respiratory chain-based mitochondrial disease ~3 per 100 000 births[9] 1 in 33,000[9]
Glycogen storage disease 2.3 per 100 000 births[9] 1 in 43,000[9]


  1. MedlinePlus Encyclopedia: Inborn errors of metabolism
  2. "Inherited metabolic disorders - Symptoms and causes". Mayo Clinic. Archived from the original on 2023-01-31. Retrieved 2023-03-27.
  3. Garrod, Archibald E (1923). Inborn errors of metabolism. OCLC 1159473729. Archived from the original on 2017-07-23. Retrieved 2023-03-27.[page needed][non-primary source needed]
  4. Bartolozzi, Giorgio (2008). "Errori congeniti del metabolismo" [Inborn errors of metabolism] (PDF). Pediatria: principi e Pratica clinica [Pediatrics: Principles and Clinical Practice] (in Italian). pp. 361–386. ISBN 978-88-214-3204-0. OCLC 884592549. Archived (PDF) from the original on 2023-03-19. Retrieved 2023-03-27.{{cite book}}: CS1 maint: unrecognized language (link)
  5. Sghirlanzoni, Angelo (2010). Terapia delle malattie neurologiche. doi:10.1007/978-88-470-1120-5. ISBN 978-88-470-1119-9.
  6. Geerdink, R.B; Niessen, W.M.A; Brinkman, U.A.Th (March 2001). "Mass spectrometric confirmation criterion for product-ion spectra generated in flow-injection analysis". Journal of Chromatography A. 910 (2): 291–300. doi:10.1016/s0021-9673(00)01221-8. PMID 11261724.
  7. Vernon, Hilary J. (1 August 2015). "Inborn Errors of Metabolism: Advances in Diagnosis and Therapy". JAMA Pediatrics. 169 (8): 778–782. doi:10.1001/jamapediatrics.2015.0754. PMID 26075348.
  8. Cannon Homaei S, Barone H, Kleppe R, Betari N, Reif A, Haavik J (2021). "ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications". Neuroscience and Biobehavioral Reviews. 132: 838–856. doi:10.1016/j.neubiorev.2021.11.012. PMID 34774900. S2CID 243983688.
  9. 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 Applegarth, Derek A.; Toone, Jennifer R.; Lowry, R. Brian (1 January 2000). "Incidence of Inborn Errors of Metabolism in British Columbia, 1969–1996". Pediatrics. 105 (1): e10. doi:10.1542/peds.105.1.e10. PMID 10617747.
  10. Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma. del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo (May 2017). "Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system". Molecular Genetics and Metabolism. 121 (1): 16–21. doi:10.1016/j.ymgme.2017.03.001. PMID 28302345.

Further reading

  • Price, Nicholas C; Stevens, Lewis (1996). Principi di enzimologia [Principles of enzymology] (in italiano). A. Delfino. ISBN 978-88-7287-100-3. OCLC 879866185.
  • Mazzucato, Fernando; Giovagnoni, Andrea (2019). Manuale di tecnica, metodologia e anatomia radiografica tradizionali [Manual of traditional radiographic technique, methodology and anatomy] (in italiano). Piccin. ISBN 978-88-299-2959-7. OCLC 1141547603.
  • Torricelli, P; Antonelli, F; Ferorelli, P; Borromeo, I; Shevchenko, A; Lenzi, S; De Martino, A (March 2020). "Oral nutritional supplement prevents weight loss and reduces side effects in patients in advanced lung cancer chemotherapy". Amino Acids. 52 (3): 445–451. doi:10.1007/s00726-020-02822-7. PMID 32034492. S2CID 211053578.

External links

External resources