Systems biology and inborn error of metabolism: analytical strategy in investigating different biochemical/ genetic parameters

Inborn errors of metabolism (IEM) are a group of about 500 rare genetic diseases with large diversity and complexity of the metabolic pathways involved. The result of this variability is the difficulty of establishing the correct diagnosis. However, a correct and rapid diagnosis is usually mandatory for successful treatment. IEM are genetic disorders causing from defects in a given biochemical pathway and for this reason is difficult to determinate a diagnosis. In fact, in contrast with Garrod’s theory of “one-gene one-disease”, no simple correlation between genotype–phenotype have been vindicated in IEMs. An illustrative example of IEM is Phenylketonuria (PKU), an autosomal recessive inborn error of L-phenylalanine (Phe), ascribed to variants of the phenylalanine hydroxylase (PAH) gene encoding for the enzyme complex phenylalanine hydroxylase. The blood values of Phe allow to classify PKU into different clinical phenotypes. However, it has been shown that the most serious complications, such as cognitive impairment, are not only related to the gene dysfunction but also to the patient's background and the participation of several non-genetic factors. For this, Systems Biology is useful to understand IEM complexity and to determinate the correct diagnosis. In fact, it can be defined as a holistic and systemic analysis of complex system inter-connections and their functional interrelationships. Therefore, with different systemic approaches, like genomics, transcriptomics, proteomics and metabolomics, it is possible to determine the origin of the pathology and to approach it in a targeted way for the patient.