Alberto J. L. Macario, and Everly Conway de Macario
Summary
Inherited metabolic syndromes caused by enzymatic deficiencies are typically detected through newborn screening. In most cases, a mutation in the gene encoding the defective enzyme is the pathogenic factor. However there are cases, the frequency of which is currently unknown but it can be assumed to be considerable, in which a defect in the chaperoning system contributes to disease development. The chaperoning system is responsible for the correct folding of enzymes and for maintaining their functional configuration and assembly but when a chaperone is defective the pertinent enzyme is totally or partially inactive. It is now known that in some metabolic syndromes the enzymopathy is caused by chaperone deficiency; it is in fact a genetic chaperonopathy with the gene encoding the enzyme being normal but its product is abnormal due to improper chaperoning. Likewise, cases of autoinflammation caused by mutation of the gene encoding the anti inflammation protein pyrin can be complicated by a concomitant mutation in the gene encoding the ER chaperone TRAP1. This is an example of diseases considered monogenic that can in fact be sometimes digenic: a chaperonopathy acts as a second pathogenic factor, making the clinical-pathological picture very severe. These chaperonopathies can be classified as hidden because they are overshadowed by a clinical-pathological picture characteristic of a known condition typically not linked to a failure of the chaperone system. Physicians and pathologists should be on the alert toward diagnosing chaperonopathies because patients will greatly benefit by proper treatment, including chaperonotherapy.
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