Inborn errors of metabolism

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Biodynamic Enzymology[edit]

Inborn errors of metabolism
SpecialtyMedical genetics Edit this on Wikidata

Biodynamic Enzymology enhances - at this historical moment in which science is focused on "omics" (genomics, transcriptomic, proteomics, lipidomics, etc.) - the central metabolic role of enzymes, the real workers from whose silent and tireless work depends the well-being of all cells and, when operating in abnormal way, follows the trigger of reactive or degenerative processes capable of compromising the quality and / or duration of any organism.

Nucleotides (DNA structure) consist of three characteristic groups: a nitrogen base, a pentangle and a phosphoric group.

These components are synthesized by enzymes with the consequent nucleotide assembly by mRNA (Ribonucleic Acid).

Inborn errors of metabolism or Enzymopathy, form a large class of genetic diseases involving congenital disorders of metabolism.[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] The term inborn errors of metabolism was coined 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]

Overcoming the Dogma of Biology[edit]

The in-depth study of biology and branches connected to it is now focused on the use of predefined and well-established concepts. The same dogma of biology states that life starts from DNA and therefore does not take into account what's before. The DNA is in fact the product of a series of chemical reactions that start from the atom and that are extended thanks to the help of the enzymes. From this point of view we should focus the study of the subject starting from the main elements of life and not by DNA, this being a derived product.

The Enzyme Approach[edit]

Enzymes are a proteinic macromolecules in which the structure is a depository of "memories", interactive with specific substrates. The initial study on enzymes assumed the active site of the enzyme as a rigid structure and the adaptation of a substrate in the active site more or less like a key in the lock. This first idea was suggested for the first time in 1894 by the German biochemist Emil Fischer.

In a model structured in this way, or according to the "key and lock" version it was possible to guess how the enzymes were specific and coordinated between them. A more useful view of enzyme-substrate interaction derives from the model of induced adaptation. This model assumes that the initial link of the substrate molecule to the active site will distort both the enzyme and the substrate, stabilizing the molecule of the latter in its transition state and thus making the link more susceptible to the catalytic attack.

The Role of the Enzymes[edit]

Enzymes are biological catalysts that allow to accelerate chemical reactions, or the speed with which they take place. In all living systems the purpose of the processes produced by enzymes is to reach the balance of an energy system that in this case makes the cells and then to the referenced organs of the body. In fact, the enzymes allow the achievement of a given order (defined system enthalpy that contrasts non-harmonious disorder when we speak, of the contrary: entropy.

To get an idea of how many enzymes are present in the human body just think that about 80% of proteins present in the human body are enzymes. As a result, intra-cellular reactions that take place in the cells are, mostly, facilitated and therefore accelerated by enzymes.

The Quaternary Conformation of Proteins[edit]

The arrangements of proteins and protein sub-units in three-dimensional complexes constitutes the so-called quaternary structure; Integrations between sub-units are stabilized and driven by the same forces that stabilize the tertiary structure, which can be attributed to non-covalent multiple interactions. The first oligomeric protein to be subjected to X-ray analysis was the hemoglobin that contains four EME polypeptide chains, in which iron atoms are in ferrous state; The protein part, called globin, consists of two chains (each of 141 residues) and from two chains (each of 146 residues) and do not refer in this case to the secondary structures of proteins.

The hemoglobin molecule is almost spherical, with a diameter of about 5.5 nm; The chains contain several propeller segments separated by foldings and their tertiary structure is very similar to that of the monomeric myoglobin protein. The way of wrapping and folding a polypeptide chain is long and obviously complicated and the principles that drive this process have not yet been identified in detail; Most proteins fall spontaneously in their right conformation, this behavior confirms that all data concerning the conformation must be contained in the same sequence of amino acids.

One of the most important factors that govern the way to fold up a polypeptide lies in the distribution of its polar and non-polar side chains; While the protein is synthesized its various hydrophobic side chains tend to be segregated within the molecule, at the same time all the polar side chains tend to dispose near the external portion of the protein molecule, where they are able to interact with the water and other polar groups.

Being polar the same peptide bonds, these tend to interact both with the polar side chains with each other through hydrogen bonds; Almost all the residues of polar characteristic situated in depth inside the protein are coupled in this way.

The Importance of Enzymes in Diagnostics[edit]

Diagnostic with enzymes

Because the measure of an enzymatic activity is useful for a clinical routine diagnosis the following conditions must be met.

1. The enzyme must be present in the blood, in the urine, or in other tissue fluids that can be easily found. Textile biopsies should not be practiced as routine, but only in cases where the diagnostic value is particularly important.

2. The enzyme must be easily dosable and is even better if the method can be automated.

3. The quantitative differences between the enzymatic activities of normal and sick subjects must be significant, and there must be a good correlation between the levels of enzymatic activity and the pathological state.

4. It is also advisable that the enzyme is sufficiently stable to allow sample conservation at least for limited periods of time.

The serum is the fluid on which most analysis are done. Urine can only be used for few enzymes secreted by the kidneys. Red blood cells and white blood cells, despite their availability, until today are not very used in diagnosis.

The enzymes in the serum can be divided into two categories: (i) specific plasma enzymes and (ii) non-specific plasma enzymes.

  • The first category includes those enzymes that carry out a plasma activity, such as enzymes involved in blood coagulation, in the activation of the complement, and in the metabolism of lipoproteins.
  • The second category includes those enzymes that do not carry out physiological functions in the plasma; Enzymes for which both the cofactors and substrates may be missing. This category includes the enzymes secreted by the tissues: amylase, lipase, phosphatase and other enzymes associated with cellular metabolism, whose presence in a normal serum in low quantity can be attributed to the normal cellular replacement of the fabric with consequent release of the enzymatic content.

The enzymatic dosage for diagnostic purposes is justified in the fact that if the fabric is damaged or produces an excessive amount of intracellular enzymes, there will be an increase in related enzyme activities in the serum.

For some enzymes the concentration gradient between the interior of the cell membrane and the extracellular fluid is very high (of the order of 10³ or even greater) for which to a minimum damage of the fabric corresponds to a considerable increase in some serum enzymes.

Several studies of Italian Scientist Ferorelli P.  have determined and developed a new technique, by means of components (substrates) obtained from the transformation of specific genetic enzymes, this leads all endogenous enzymes to modulate reactions consistently with the principles of thermodynamics. Improving species in pathological conditions some tissue can be inflamed or about to reach necrosis, in this case you will have the complete release of enzymes by the dead cell.

In any case, the distribution of enzymes found in the serum may also not reflect that of the original tissue since the enzymes can be inactive with different speed. It can happen that the inflammation of a tissue leads to a variation of cellular permeability such as to cause the release of cytosol enzymes and not those belonging to the organelles, such as the glutamate dehydrogenase, present in high concentration in the mitochondrial matrix, which is released only when the cell distribution is almost complete.

Enzymes released in the serum are removed quite quickly with a mechanism not yet completely clarified; It could be phenomena of inactivation and degradation that take place in the serum or even a removal from the kidney.

To study the fate of the enzymes in the serum experiments were conducted by injecting intravenous in lactate dehydrogenase rabbits (LDH-5) marked with 125. The results obtained suggest that the LDH- is denatured in the plasma and the products are excreted in the tenuous intestine where they are further degraded to be reabsorbed, such as amino acids or small peptides, in blood circulation.

The rapid removal of most enzymes means that following the presence of a given enzyme in a patient's serum provides an updated picture of tissue damage. It follows that the dosage of enzymes in the serum is useful not only for an initial diagnosis but also to follow the trend of the disease and the response to treatment.

Ideally, for diagnostic purposes, it would be desirable to analyze specific tissues that would allow to identify the tissue from which they come; But the enzymes are relatively few, although some are more abundant in particulate tissues, as it takes place for acid phosphatase in prostate or acetylcholinesterase in erythrocytes. Although not a particular enzymatic activity for a specific tissue, it can exist isoenzymes that have a different distribution in various tissues.

The most studied case is that of the dehydrogenase lactate. The enzyme consists of four subunits. There are two types of subunits that, combining in various ways, give rise to five different forms of lactate dehydrogenase ɑ1ß, ɑ2ß, ß3, ɑß4, and ß5.

These five forms, separable electrophoretically, are differently distributed in tissues (figure 1). In this way, although through the dosage of the activity of the dehydrogenase lactase present in the serum it is not possible to go back to the original tissue, the identification may be possible if the isoenzymatic distribution is determined by electrophoresis. Also for other enzymes in the serum we know multiple forms, such as alkaline phosphatase, amylase, creatine kinase, ceruloplasmin, 6-phosphate dehydrogenase glucose and aspartatransferase, but none of these isoenzymes was well characterized as the lactate dehydrogenase.

Some of these isoenzymes can be identified with methods other than electrophoretic mobility, such as specificity (Figure 1). Today it is possible, in some cases, to distinguish the isoenzymes, make use of monoclonal antibodies. This method has been applied to recognize the different isoenzymes of human phospho fruttochinase, and to identify what was the absent form in the hereditary deficiencies of phospho fruttochinase.

Monoclonal antibodies against specific isoenzymes will be used in the future to be used to identify and quantify isoenzymes used as tumor markers, such as acid phosphatase in prostate, the alkaline phosphatase of the placenta and the desoxinucleotide terminal transfer.

In many cases, where enzymatic activity dosages are used for diagnostic purposes, more than one enzymatic activity is tested for correct evaluation. Liver and cardiac diseases represent the two cases in which enzymatic analysis was particularly useful and is most widely used. It should be pointed out that enzymatic activity dosages are not sufficient to make a diagnosis but must be evaluated together with clinical symptoms and other types of evidence, such as the electrocardiogram, in the case of cardiac damage. The increase of activities in some serum is a common phenomenon in neoplasms, although no enzyme is specific to cancer and, until now, no dosage detected has been useful for an early tumor diagnosis.

The isoenzymatic representations, in addition to give us indications on the origin of the tissue, are also useful in legal medicine. Since numerous enzymes of the serum and of the red blood cells are present in different isoenzimatic forms, the particular distribution in a blood sample can help to identify its origin.

The isoenzymatic representations that are normally used by the Metropolitan Police Science Laboratory are those of adenosine deaminase, adenylated kinase, dehydrate carbonate, acid phosphatase, extrerasy, phospho-glucomutasi, aminopeptidase and lactilglutionione Liasi.


Traditionally the inherited metabolic diseases were classified as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. 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. Many others do not fall into these categories.[citation needed]

Signs and symptoms[edit]

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. This is an increasingly common way for the diagnosis to be made and sometimes results in earlier treatment and a better outcome. There is a revolutionary 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. 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 [6]

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 2017-02-27.
  2. ^ "Inherited metabolic disorders - Symptoms and causes". Mayo Clinic.
  3. ^ Archibald Garrod. 1923. Inborn Errors of Metabolism at Electronic Scholarly Publishing site
  4. ^ Cantú-Reyna, C.; Santos-Guzmán, J.; Cruz-Camino, H.; Vazquez Cantu, D.L.; Góngora-Cortéz, J.J.; Gutiérrez-Castillo, A. (4 February 2019). "Glucose-6-Phosphate dehydrogenase deficiency incidence in a Hispanic population". Journal of Neonatal-Perinatal Medicine. 12 (2): 203–207. doi:10.3233/NPM-1831. PMID 30741698.
  5. ^ Zea-Rey, Alexandra V.; Cruz-Camino, Héctor; Vazquez-Cantu, Diana L.; Gutiérrez-García, Valeria M.; Santos-Guzmán, Jesús; Cantú-Reyna, Consuelo (27 November 2017). "The Incidence of Transient Neonatal Tyrosinemia Within a Mexican Population". Journal of Inborn Errors of Metabolism and Screening. 5: 232640981774423. doi:10.1177/2326409817744230.
  6. ^ a b 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.
  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.

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