Mitochondrial diseases are a group of rare diseases affecting energy production in cells and can therefore impair the functioning of many organs.
More than 1,800 hereditary metabolic disorders have been identified.
Metabolism involves thousands of proteins, mainly enzymes, cofactors, receptors, and transporters, whose deficiencies are responsible for a hereditary metabolic disorder. Until recently, the focus was primarily on disorders affecting the catabolism of molecules, while defects in synthesis and transport were markedly underrepresented or even ignored. Thanks to the development of high-throughput sequencing, the number of recognised hereditary metabolic disorders has increased very rapidly. Today, a disorder is considered a hereditary metabolic disorder as soon as a deficiency of a specific enzyme or metabolic pathway lies at the core of the disease’s pathophysiology.
The most recent classification of hereditary metabolic disorders is the International Classification of Inherited Metabolic Disorders (ICIMD, Ferreira et al., Journal of Inherited Metabolic Disorders, 2021), in which our group participated. It is based on biochemical categories (synthesis, remodeling, transport, catabolic defects, and intracellular trafficking) rather than the previous organelle-based approach, which arbitrarily divided metabolic pathways. In 2021, the ICIMD included nearly 1,500 hereditary metabolic disorders. Today, this number continues to rise, approaching 1,800 disorders. It is important to note that more than two-thirds of these disorders present neurological symptoms, including in adults.
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How can one navigate inherited metabolic disorders?
To help clinicians navigate the wide range of inherited metabolic disorders, we contributed to a simplified classification approach based on three groups (Saudubray et al., Journal of Inherited Metabolic Disorders, 2019). These 3 groups – disorders related to small molecules, disorders related to complex molecules, and energy metabolism disorders – correspond both to similar clinical presentations and to comparable pathophysiological mechanisms.
Within these 3 categories, a further distinction is made between diseases caused by the accumulation or deficiency of molecules, as well as abnormalities of cellular transport and trafficking. Disorders associated with the accumulation of small molecules (also referred to as intoxication disorders) are often post-natal in onset, have specific biochemical markers, and are treatable. By contrast, disorders related to defects in complex molecules may begin in the neonatal period and currently remain largely inaccessible to effective treatments.
How are neurometabolic disorders diagnosed?
Despite the major expansion of molecular biology, the diagnosis of neurometabolic disorders still relies primarily on metabolic biomarkers obtained through biochemical assays. Some of these biomarkers are specific to particular inherited metabolic disorders, while others point towards a broader group of neurometabolic diseases. The results of these assays can be obtained within a few hours to a few days, which is particularly important for initiating emergency treatments, especially in intoxication disorders.
Biomarkers are also used to monitor the response to metabolic therapies. These biochemical investigations are always complemented by genetic analyses. For some neurometabolic disorders, no biomarkers are currently available, and diagnosis therefore relies entirely on molecular testing.
Once a diagnosis has been established, a family investigation (genetic counselling) is offered in order to identify relatives who may be at risk of developing the disorder or transmitting it to their offspring.
What treatments are available for neurometabolic disorders?
Inherited metabolic disorders are distinctive among rare diseases—often described as “orphan diseases” because of the lack of available treatments—in that a number of therapeutic approaches can be effective. The impact of these treatments may be substantial, which is why many of the rare diseases included in neonatal screening programs are inherited metabolic disorders. These therapeutic approaches include, although not exhaustively:
- Dietary interventions. For example, in phenylketonuria, a low-protein diet with controlled phenylalanine intake, initiated from the neonatal period, allows patients to achieve normal psychomotor development and reach adulthood without neurological disability. Another example is the ketogenic diet (very high in fat in order to promote the production of large amounts of ketone bodies) used in GLUT1 glucose transporter deficiency.
- Cofactors such as vitamins. For instance, in biotinidase deficiency, early treatment with biotin (vitamin B8) leads to complete resolution of neurological symptoms. This is also the case for vitamin-responsive forms of homocystinuria (due to cystathionine beta-synthase deficiency), which respond well to treatment with vitamin B6.
- Small molecules that correct the altered metabolic pathway. These may act by removing a toxic metabolite—for example, the reduction of ammonium with sodium benzoate in hyperammonaemia—or through inhibitory feedback mechanisms that help correct toxic metabolites, as in treatment with chenodeoxycholic acid in cerebrotendinous xanthomatosis.
- Enzyme replacement or correction. This may involve direct administration of the missing enzyme (for example pegzilarginase in arginase deficiency) or organ transplantation, such as liver transplantation in urea cycle disorders.
- Gene therapies, which are currently under clinical investigation for an increasing number of neurometabolic diseases.
In addition, in all neurometabolic disorders, symptomatic treatments may be provided—pharmacological and/or rehabilitative—to improve symptoms such as spasticity, pain, or psychiatric manifestations.
Different types of neurometabolic diseases
Disorders of Complex Lipids and Intracellular Trafficking
Complex lipid disorders are hereditary conditions caused by defects in the metabolism of lipids that are essential for cell membrane structure and intracellular transport.
Creatine Deficiency Disorders
Creatine metabolism disorders are inherited conditions leading to a cerebral creatine deficiency due to impaired synthesis or transport.
Glut1 deficiency syndrome
GLUT1 deficiency syndrome is a neurometabolic disorder caused by impaired glucose transport into brain glial cells, leading to a deficiency in brain energy supply.