Inborn Metabolic Diseases, called also Inborn Errors of Metabolism, are a large group of genetic diseases caused by malfunctioning of a specific metabolic pathway.
A metabolic pathway is a number of processes, by mean of a sequence of chemical reactions, which happens in human body on products of dietary or endogenous origin with the aim of make its available or avoid their accumulation. These metabolic processes are fundamental to produce essential compounds, to remove toxic compounds from body organs or to produce energy inside the cells. Almost all these reaction are possible by means of the activity of enzymes (usually proteins) which often needs a cofactor (vitamins, oligoelements, others).
A Metabolic Disease can be the consequence of the malfunction of a specific enzyme (due to a structural or functional modification of the protein or of the cofactor) or of abnormalities of cellular transport mechanisms.
The relevant consequences of the block of the metabolic pathway can be:
- the accumulation of compounds (precursors) located before the biochemical defect which leads to toxic effects;
- absence, or dearth, of the final products of the metabolic pathway (metabolites), which can lead to a defect on essential substrates or abnormalities in energy production;
- activation of alternative pathways with production of potentially toxic metabolites usually non present in human body.
The subsequent clinical picture, varying with the metabolic defect, is due to the accumulation of toxic compounds, to the lack on an essential product, or, finally to the lack of energy. It is possible that all above described mechanisms coexist.
Due the complexity of biological events, metabolic diseases present, in the majority of cases, with systemic symptoms, involving more organs and apparatuses. The involvement of the central nervous system is very frequent while the involvement of a single organ is rare. With reference to the mechanism of intoxication, it can be acute or chronic and slowly progressive.
In the first case the clinical signs are very severe and need intensive interventions. A Metabolic Disease can, generally, present at any age, from the foetus to the adult. However, the appearance of the clinical signs is more frequent in newborn and childhood. The clinical onset can be, following the specific metabolic disease, acute (usually at birth or subsequent to a triggering event), or late-onset due to the chronic intoxication.
Metabolic disorders can roughly divided in the following categories:
- disorders causing intoxication (acute or chronic);
- disorders of energy production and utilisation;
- disorders of lack of substrates;
- disorders of the metabolism of complex molecules.
The basis of a Metabolic Disease is a genetic defect (DNA mutation) which is the cause of the failure in production of a specific enzyme or cofactor, or their production as non-functional form.
Concerning the inheritance, Metabolic Disorders are, in general autosomal recessive (both parents are health carriers of a mutation); a few defects are subsequent to a mutation located on the X chromosome, are of maternal inheritance and are called X-linked.
The inheritance-mode of respiratory chain defects is more heterogeneous: the sub-units (parts) of these enzymatic complexes are encoded partly by nuclear genes (almost all with autosomal recessive inheritance), partly by mitochondrial DNA with maternal inheritance.
The compounds which accumulates or are not produced as consequence of a metabolic block (biomarkers), can be assayed by sophisticated laboratory investigations in biological fluids (blood, urine, cerebrospinal fluid). Diagnosis is, firstly, based on the measurement of these critical metabolites and, then, in enzyme or genetic studies. It must be underlined that the diagnosis of a metabolic disorder is a tricky process which needs of a full synthesis between the clinical picture and the biomarker profile and must be performed only in learned Centres with established expertise and experience. Early diagnosis is of high value for the prognosis, while (in treatable disorders) it allows prompt and specific treatment and can avoid the clinical harms subsequent to the onset or worsening of the disease.
In the last years the technology advances opened the door to newborn screening for a large number of metabolic disorders, allowing diagnosis and treatment at neonatal stage, before the onset of the clinical signs.
Most of Metabolic Disorders respond to a specific treatment (diet and/or drugs) which, like the diagnostic process, must be managed by learned Centres with established expertise and experience. For some Metabolic Disorders the treatment includes transplantation, i.e. bone marrow stem cells or liver transplantation.