Inherited metabolic disorders, also known as inborn errors of metabolism, are a category of genetic diseases caused by the impaired function of specific metabolic pathways.
A metabolic pathway is a sequence of biochemical transformations that normally occur within the human body. Through these sequential biochemical reactions, food-derived products or pre-existing compounds are either converted into usable forms or their accumulation is prevented.
These metabolic processes are crucial for producing essential substances, eliminating toxic compounds from various organs, and generating energy within cells.
Almost all of these reactions are catalysed by an enzyme (typically a protein), which often works alongside a cofactor (such as vitamins, trace elements, etc.).
A metabolic disorder may develop from either the malfunction of an enzyme, caused by structural or functional changes in the protein or cofactor, or from disruptions in cellular transport mechanisms. The consequences of a blocked metabolic pathway can include:
- The accumulation of compounds (precursors) upstream of the biochemical defect, which may become toxic
- A deficiency or absence of the final products of the metabolic pathway (metabolites), leading to a shortage of essential substrates or disruptions in energy production
- The activation of alternative metabolic pathways by the body, potentially producing secondary metabolites that are normally absent in the human body, which can also be toxic.
The resulting clinical symptoms, which vary according to the specific metabolic defect, are due either to the toxicity of accumulated metabolites, the lack of an essential product that is not synthesised, or the deficit of energy. All of the mechanisms described above can coexist, and, given the complexity of biological processes, these disorders often present with systemic symptoms, affecting multiple organs and systems. Damage to the nervous system is common, whereas diseases that affect only a single organ (the so-called target organ) are rarer.
The intoxication mechanism can be either acute or chronic and progressively worsening.
When it is acute, clinical manifestations are very severe and require intensive intervention.
Metabolic disorders can manifest at any stage of life, from the foetal period to adulthood. However, it is more common to observe symptoms in childhood.
The clinical onset can vary, depending on the type of metabolic defect, and may be acute (typically neonatal or triggered by an event) or delayed, resulting from the gradual accumulation of toxins over time. Hereditary metabolic disorders can be broadly classified into the following categories:
- Storage diseases causing poisoning (either acute or chronic)
- Energy metabolism disorders
- Substrate deficiency diseases
- Disorders of complex molecule metabolism
The underlying cause of the metabolic defect is always genetic (a mutation in the DNA) that leads to the failure to produce an enzyme or its cofactor, or to the production of a non-functional version.
In terms of genetic inheritance, metabolic disorders are generally transmitted in an autosomal recessive manner (both parents are carriers of a mutation). Some defects result from mutations in genes located on the X chromosome, which are maternally inherited, and are referred to as X-linked.
The hereditary mechanisms responsible for mitochondrial respiratory chain defects are more heterogeneous, as the various components (subunits) constituting these enzymatic complexes are encoded by both nuclear genes—typically inherited in an autosomal recessive manner—and mitochondrial DNA passed down from the mother.
The accumulated or insufficiently produced compounds in metabolic disorders, known as biomarkers, can be detected through sophisticated laboratory tests using biological fluids from patients (blood, urine, cerebrospinal fluid).
Diagnosis begins with measuring these specific metabolites, followed by enzyme activity testing and genetic analysis.
It is important to note that diagnosing a metabolic disorder is a delicate and complex process that requires integration of the clinical symptoms with the biomarker profile. For this reason, it is essential to seek out specialist centres with proven expertise and experience.
Early diagnosis is of great prognostic value, as it enables prompt initiation of specific treatment for treatable diseases, helping to prevent clinical damage caused by the disorder or its worsening.
Recent technological advancements have made neonatal screening for a broad range of metabolic disorders possible, enabling early diagnosis and treatment during the neonatal period, before symptoms appear.
For many metabolic disorders, specific treatments (either dietary and/or pharmacological) are available, and much like the diagnostic process, these must be carried out at a specialist centre.
For some metabolic disorders, treatment may involve transplantation, such as stem cell transplants from bone marrow or liver transplants.