IMDs
Inherited Metabolic Disorders
In the European Union, life-threatening or chronically debilitating conditions with a low prevalence in the population, affecting fewer than 5 in 10000 people, are considered to be rare (Decision No 1295/1999/EC)
Taken individually, each rare disease affects a very small fraction of European population. Taken together, instead, rare diseases are a conspicuous group of approximately 6000-8000 diseases and they therefore constitute a huge healthcare issue. An estimated 36 million individuals currently live with a rare disease in the EU and around 80% of these conditions are thought to have a genetic origin.
Inherited Metabolic Disorders (IMDs), in particular, represent a group of more than 1400 rare genetic pathologies, classified in 130 different biochemical groups, that impact both children and adults and are quite heterogeneous. In fact, clinical presentations can vary a lot among different IMDs in terms of symptoms and course of the disease. Metabolic disorders are generally chronic and progressive and can involve multiple organs, thus early diagnosis and treatment are crucial to avoid further complications.
IMDs are a complex class of conditions that can affect the metabolism of carbohydrates, amino acids, lipids, steroids but also nucleic acids, mitochondria and neurotransmitters. Optimal care for patients with rare metabolic disorders can be achieved only through a joint effort.
Diseases groups
- 1. Disorders of intermediary metabolism
- 2. Disorders of lipid metabolism and transport
- 3. Disorders of heterocyclic compounds
- 4. Disorders affecting the metabolism of complex macromolecules and organelles
- 5. Disorders of the metabolism of cofactors and minerals
- 6. Disorders of metabolic cell signaling
1. Disorders Of intermediary metabolism
Intermediary metabolism is defined as the full set of reactions that transform nutritive materials into energy storage compounds, reducing equivalents and biosynthetic intermediates. Disorders of intermediary metabolites involve pathways that mediate the breakdown of low-molecular weight nutrient compounds (such as proteins, carbohydrates, and lipids) or convert them into substrates for the biosynthesis of complex molecules. Intermediary metabolism disorders might also comprise diseases of mitochondrial oxidative phosphorylation, including disorders affecting mitochondrial DNA maintenance and gene expression, import, dynamics and cofactor biosynthesis.
- 1.1 Disorders of amino acid metabolism
- 1.2 Disorders of peptide and amine metabolism
- 1.3 Disorders of carbohydrate metabolism
- 1.4 Disorders of fatty acid and ketone body metabolism
- 1.5 Disorders of energy substrate metabolismNew
- 1.6 Mitochondrial DNA-related disorders
- 1.7 Nuclear-encoded disorders of oxidative phosphorylation
- 1.8 Disorders of mitochondrial cofactor biosynthesis
- 1.9 Disorders of mitochondrial DNA maintenance and replication
- 1.10 Disorders of mitochondrial gene expression
- 1.11 Other disorders of mitochondrial function
- 1.12 Disorders of metabolite repair/proofreading
- 1.13 Miscellaneous disorders of intermediary metabolism
1.1 Disorders of amino acid metabolism
This group encompasses many metabolic disorders which are identifiable through standard metabolic assessments, such as amino acids and organic acids analysis, and are often responsive to dietary interventions. Disorders of amino acid metabolism include, between others, homocystinuria, Hartnup disease, phenylketonuria and tyrosinemia.
1.2 Disorders of peptide and amine metabolism
This small group of disorders comprises deficiencies of enzymes which are involved in the biosynthesis and regeneration of glutathione, a critical molecule in protecting cells from oxidative stress. In addition, this group also includes disorders linked to dipeptidase deficiencies and issues in the metabolism of methylamine and polyamine metabolism.
1.3 Disorders of carbohydrate metabolism
Disorders affecting carbohydrate metabolism represent a diverse group of conditions with varying clinical presentations. These disorders can be categorised based on either deficiencies or hyperactivity of specific enzymes involved in carbohydrate metabolism. Thus, they can impact various pathways, including the metabolism of galactose, fructose, and glycogen. Moreover, these conditions may affext glycolysis, gluconeogenesis, and transmembrane transport and absorption.
1.4 Disorders of fatty acid and ketone body metabolism
This group of conditions includes disorders of mitochondrial fatty acid oxidation, carnitine metabolism, and also ketone body synthesis, breakdown and transport.
Clinically, mobilisation of stored triglycerides during fasting or prolonged exercise results in the hepatic production of ketone bodies, which serve as an energy source when glucose is not readily available, in particular for muscles and brain. Brain has in fact a high energy demand but has a limited ability to use fatty acids as energy source, so ketone bodies (which are produced starting from fatty acids) are able to provide the brain with an alternative source of energy.
The main ketone bodies are acetoacetate (AcAc), 3-β-hydroxybutyrate (3HB) and acetone. Abnormally large quantities of ketone bodies can be found in the blood of patients with diabetic ketoacidosis, alcoholic ketoacidosis and some other rare conditions.
1.5 Disorders of energy substrate metabolismNew
This group of disorders combines disorders of pyruvate metabolism, disorders of the Krebs cycle as well as creatine metabolism disorders.
The products of amino acid, carbohydrate, and lipid breakdown are transported into the mitochondria where they serve as substrates for adenosine triphosphate (ATP) synthesis by the process of oxidative phosphorylation. This process is essential to cells, as ATP serves as the main energy source to fuel various biological functions, from muscle contraction to nerve impulse transmission.
These disorders are generally due to deficiency of several enzymes or molecule transporters, leading to the accumulation of toxic intermediates which can disrupt the normal functions of cells.
1.6 Mitochondrial DNA-related disorders
Mitochondrial disorders were first genetically characterized by identifying deletions and point mutations within mithochondrial DNA (mtDNA).
Before a cell expresses an abnormal phenotype, the proportion of mtDNA pathogenic variants must exceed a critical threshold level. Additionally, there might also be different tissue segregation patterns of pathogenic mtDNA variants and mtDNA exists in multiple copies per cell. For these reasons, clinical phenotypes of mtDNA disorders are quite different from one patient to another.
Mitochondrial DNA disorders have been classificed in three subgroups, encompassing disorders associated with protein-coding genes, genes encoding mitochondrial tRNAs and rRNAs, and disorders associated with single large-scale mtDNA deletions.
1.7 Nuclear-encoded disorders of oxidative phosphorylation
This group of disorders includes deficiencies of subunits and assembly factors of the five oxidative phosphorylation complexes (found in the inner mitochondrial membrane) whose encoding genes are located in the nuclear DNA. This defects are generally associated with deficiencies of single enzyme complexes in the affected tissues and they can disrupting the oxidative phosphorylation pathway.
The clinical manifestations of these disorders are highly variable and can include symptoms such ar weakness, exercise intolerance, neurological deficits, lactic acidosis, and multi-organ failure.
1.8 Disorders of mitochondrial cofactor biosynthesis
This group includes disorders affecting the biosynthesis of the following cofactors , which are exclusively expressed in the mitochondria : coenzyme Q10 (ubiquinone), lipoic acid, iron-sulphur clusters and cytochrome c. Clinical manifestations o f these kinds of deficiencies range from fatal multisystem disorders, isolated encephelopathy or nephropathy, brain abnormalities to seizures. Disorders belonging to this group are typically characterized by diminished ATP and an increase in reactive oxygen species ( ROS) production.
1.9 Disorders of mitochondrial DNA maintenance and replication
This category comprises diseases affecting both proteins needed for mitochondrial nucleotide pool maintenance and proteins which are instead essential for mtDNA replication and maintenance. In the case of mitochondrial deoxyguanosine kinase deficiency, an unbalanced pool of dNTPs for the reduction of deoxypurines leads to mtDNA single or multiple deletions. Mitochondrial thymidine kinase deficiency might lead to similar outcomes, causing myopathic weakness and severe depletion of muscle mitochondrial DNA which have different prevalence depending on the age of onset. Other diseases, such as SAMHD1 deficiency, can instead involve the nervous system or cause hepatosplenomegaly and hematological disturbances.
1.10 Disorders of mitochondrial gene expression
This rapidly expanding group of now more than 60 conditions includes disorders that impact mitochondrial transcription and translation. These can affect mitochondrial transcript processing and modification, aminoacyl-tRNA synthetases, and the mitoribosome.The symptoms associated with these diseases can be diverse and may include fever, developmental delays, sideroblastic anemia, liver and ovarian failure, sensory neuropathy, and skeletal dysplasia.
1.11 Other disorders of mitochondrial function
This group includes disorders of mitochondrial shuttles and carriers, disorders of mitochondrial protein import, disorders of mitochondrial protein quality control, and various other mitochondrial conditions that either do not neatly fit into these categories or have yet to be fully understood. Common symptoms associated with these disorders may include epilepsy, intolerance to physical exercise, cardiomyopathy, and microcephaly.
1.12 Disorders of metabolite repair/proofreading
This group comprises a small number of diseases that are cause by deficiencies in enzymes related to metabolite repair and proofreading, both mitochondrial and non- mitochondrial. Disorders belonging to this group show variable clinical manifestations, ranging from mild to severe phenotype. Common symptoms might include failure to thrive, microcephaly, aciduria, developmental delay and dysmorphic features.
1.13 Miscellaneous disorders of intermediary metabolism
This group includes disorders of glyoxylate and oxalate metabolism, which can arise from a diverse array of metabolites, including amino acids like hydroxyproline, glycine, and serine, as well as ascorbic acid among other compounds. These disorders can lead to significant metabolic disruptions and byproducts accumulation, often affecting the kidneys, bladder, or the urinary tract.
2. Disorders of lipid metabolism and transport
Disorders of lipid metabolism and transport encompass a wide range of conditions that affect the metabolism of various lipid types (fatty acids, sphingolipids, sterol lipids) and of lipoproteins, from the first stages of biosynthesis to their transport within the body. These disorders pose a significant health burden due to increased risk for atherosclerotic cardiovascular disease.
2.1 Disorders of lipid metabolism
Disorders which are included in lipid metabolism category affect the metabolism of fatty acids, glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids. They are characterized by abnormal synthesis, breakdown, digestion, absorption and transport of lipids in the body. Such disruptions can lead to either excessive accumulation or insufficient levels of lipids in various tissues, ultimately impacting essential bodily functions.
2.2 Disorders of lipoprotein metabolism
This group of disorders includes different subgroups such as hypercholesterolemias, hypertriglyceridemias, mixed hyperlipidemias, disorders of high-density lipoprotein metabolism and disorders with decreases low-density lipoprotein or tryglicerides. These disorders have been classified depending on the type of lipid anomalies that can be observed in the blood. These disorders are often accompanied by comorbidities such as obesity, hyperglycemia, hypertension and might lead to atherosclerosis and issues with cardiovascular health.
3. Disorders of heterocyclic compounds
Heterocyclic compounds, which are organic molecules containing at least one ring structure with atoms other than carbon, play crucial roles in various biological processes. Disorders affecting heterocyclic compounds, particularly those involved in nucleotide and tetrapyrrole metabolism, can lead to severe metabolic imbalances, causing neurological symptoms, immune deficiencies, hematological abnormalities and skin conditions.
- 3.1 Disorders of nucleobase, nucleotide and nucleic acid metabolism
- 3.2 Disorders of tetrapyrrole metabolism
3.1 Disorders of nucleobase, nucleotide and nucleic acid metabolism
The group of pyrimidine and purine metabolism disorders includes disorders in the de novo synthesis, salvage and breakdown of nitrogenous bases, nucleosides and nucleotides. Additionally, this group includes disorders related to ectonucleotides, as well as the metabolism of nucleic acids, non-mitochondrial tRNA and rRNA metabolism.
These metabolic disorders can lead to various health issues, including immune deficiencies, neurodevelopmental disorders, epilepsy and muscle weakness, underscoring the critical role of nucleotide metabolism in overall cellular function and health.
3.2 Disorders of tetrapyrrole metabolism
This group includes disorders of heme synthesis, porphyrias as well as disorders involving the products of heme breakdown such as biliverdin and bilirubin. Porphyrias are caused by defective enzimatic activity in the heme biosynthetic pathway, leading to the accumulation of intermediates that genarally have an effect on the nervous system or the skin. Disorders of heme breakdown, instead, are due to deficiencies in the enzymes which are part of the degradation pathway of the heme moiety. Common symptoms include hyperbilirubinemia, hypoxia and jaundice.
4. Disorders affecting the metabolism of complex macromolecules and organelles
The proper functioning of complex macromolecules and organelles depends on the balance between biological processes, including synthesis, modification, and degradation.
When any of these processes become disrupted, it can lead to a wide range of disorders. Defects in the synthesis or modification of complex molecules can result in the production of dysfunctional or nonfunctional proteins. Similarly, issues with organelles (which are specialized compartments within cells that perform specific functions) in the processes of biogenesis, dynamics, or interactions can impair their ability to perform their essential functions, resulting in cellular dysfunctions and several clinical presentations.
- 4.1 Congenital disorders of glycosylation
- 4.2 Disorders of organelle biogenesis, dynamics and interaction
- 4.3 Disorders of complex molecule degradation
4.1 Congenital disorders of glycosylation
Congenital disorders of glycosylation (CDG) represent a diverse group of over 130 disorders stemming from defects in various stages of glycan biosynthesis and metabolism. Some defects affect only a single glycosylation pathway, while others impact several pathwahys. These disorders often manifest as multi-systemic conditions, including developmental delays, hypotonia, failure to thrive, and coagulopathy. Glycans and glycosylation have both critical biological roles in humans, as many proteins and lipids depend on carbohydrate attachment for their functionality. CDGs can affect N-linked and O-linked protein glycosylation (including glycosaminoglycan synthesis), as well as lipid glycosylation, multiple glycosylation pathways and other mechanisms related to glycan metabolism (dolichol metabolism, Golgi transport and homeostasis, sialic acid metabolism).
4.2 Disorders of organelle biogenesis, dynamics and interaction
This group consists of heterogeneous disorders which affect the biogenesis and interaction of organelles and are usually difficult to reconduct to a specific metabolic pathway. These disorders can affect mitochondria, peroxisomes, lysosomes, organelle interplay and vesicular trafficking. Such disorders can appear during infancy or early childhood, but the age of onset can vary greatly. Between the most common symptoms it is possible to find cardiomyopathy, neutropenia, growth delay, peripheral neuropathy and intellectual disability.
4.3 Disorders of complex molecule degradation
This group comprises those who are generally known as lysosomal disorders, which include deficiencies in the degradation of sphingolipids, glycosaminoglycans, glycoproteins, as well as disorders of neuronal ceroid lipofuscinosis and disorders of autophagy. The most common and known conditions belonging to this group are Gaucher disease, Nieman-Pick A and B, Fabry disease, GM2 gangliosidosis and mucopolysaccharidosis.
5. Disorders of the metabolism of cofactors and minerals
Disorders of cofactors and mineral metabolism encompass a wide range of conditions that affect the body’s ability to produce, absorb, or utilize essential vitamins, minerals, and cofactors. These substances play critical roles in various metabolic pathways by working as factors and cofactors, thus regulating and supporting essential body functions.
5.1 Disorders of vitamin and cofactor metabolism
This group includes disorders affecting the biosynthesis and transport of vitamins and cofactors such as tetrahydrobiopterin, thiamine (vitamin B1), riboflavin (vitamin B2), niacin and nicotinamide (vitamin B3), pantothenate (vitamin B5) and coenzyme A, pyridoxine (vitamin B6), biotin (vitamin B7), folate (vitamin B9), cobalamin (vitamin B12) and molybdenum cofactor.
5.2 Disorders of trace elements and metals
Disorders of trace elements and metals arise from imbalances in the levels of essential minerals such as copper, iron, manganese, and zinc. These minerals play vital roles in various biological processes, including enzyme activity, immune function, and cellular growth. Clinical presentations can range from mild to severe phenotypes. Treatment often involves dietary changes, supplements, or medications to correct the mineral imbalance.
6. Disorders of metabolic cell signaling
Metabolic cell signaling disorders encompass a wide range of conditions that disrupt the complex communication networks within cells. These disorders can affect various aspects of cellular signaling, including neurotransmitter production and signaling, and hormonal imbalances. The consequences of these disruptions can manifest as a diverse array of symptoms, including neurological problems like seizures, tremors, or cognitive impairments and endocrine dysfunction which can cause hypoglicemia, hyperinsulinemia and hyperammonemia.
6.1 Neurotransmitter disorders
Defects in neurotransmitters cause a wide range of typical neurological presentations, such as early epileptic encefalopathy, progressive pyramidal movement disorders or severe spastic diplegia. Diagnosis is generally based on quantitative determination of metabolites in the cerebrospinal fluid, including aminoacids such as glutamate, glycine and GABA and metabolites of biogenic amines and pterins.
6.2 Endocrine metabolic disorders
Endocrine metabolic disorders highlight the how metabolic and hormonal systems are interconnected. This category includes conditions affecting insulin metabolism, often overlapping with fatty acid oxidation disorders, as well as disorders involving steroid hormones derived from sterol lipids.
