Inborn Error of Metabolism
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Inborn Error of Metabolism

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 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 born following to the study of Biodynamic Enzymology, a science bases on the study of the enzymes and their derivated products. Finally, inborn errors of metabolism was studied, for the first time, by a 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]

Classification and symptoms of metabolic diseases

Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic 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].

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, which 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. 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]


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, 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,[8] overall representing more than approximately 15% of single gene disorders in the population.[8] While a Mexican study established an overall incidence of 3.4: 1000 live newborns and a carrier detection of 6.8:1000 NBS.[9]

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


  • (IT) Nicholas C. Price, Lewis Stevens, Principi di enzimologia, Antonio Delfino Editore, 1996, ISBN 887287100X.
  • (IT) Fernando Mazzucato, Andrea Giovagnoni, Manuale di tecnica, metodologia e anatomia radiografica tradizionali, Piccin, 2018.


  1. ^ "Inborn errors of metabolism: MedlinePlus Medical Encyclopedia". Retrieved .
  2. ^ "Inherited metabolic disorders - Symptoms and causes". Mayo Clinic.
  3. ^ Archibald Garrod. 1923. Inborn Errors of Metabolism at Electronic Scholarly Publishing site
  4. ^ Bartolozzi. "ERRORI CONGENITIDEL METABOLISMO" (PDF). Cite journal requires |journal= (help)
  5. ^ Uziel, Graziella; Bugiani, Marianna (2009). "Alterazioni metaboliche congenite" (PDF). Terapia delle Malattie Neurologiche. doi:10.1007/978-88-470-1120-5. ISBN 978-88-470-1119-9.
  6. ^ Geerdink, RB (2001). "Mass spectrometric confirmation criterion for product-ion spectra generated in flow-injection analysis. Environmental application". Journal of Chromatography A. 910 (2): 291-300. doi:10.1016/s0021-9673(00)01221-8. PMID 11261724.
  7. ^ Vernon, Hilary (Jun 2015). "Inborn Errors of Metabolism: Advances in Diagnosis and Therapy". JAMA Pediatrics. 169 (8): 778-82. doi:10.1001/jamapediatrics.2015.0754. PMID 26075348.
  8. ^ a b c d e f g h i j k l Applegarth DA, Toone JR, Lowry RB (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.
  9. ^ 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.

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