Toward a new and simplified pathophysiological classification of IEM
Using this extended definition a recent tentative nosology of IEM encompasses more than 1100 IEM currently identified and provisionally classified into 130 groups (Ferreira et al.
2018). This list is of little help to clinicians and has little in common with neurologists’ clinical approach. A simplified and updated classification of IEM mixes elements from the practical diagnostic approach with pathophysiological considerations into three large categories based on the size of molecules (“small and simple” or “large and complex”) and their implication in energy metabolism (Saudubray and García-Cazorla
2018).
Whatever their size, metabolites involved in IEM may behave in the brain as signalling molecules, structural components and fuels, and many metabolites have more than one role (see supplemental material Fig.
S1).
1)
Disorders of small and simple molecules
Almost all these IEM have metabolic marker(s). Their diagnosis relies on plasma, urine, and CSF investigations. Many of them can be detected by neonatal metabolic screening. There are two subcategories in small molecule disorders defined by whether the phenotype primarily results from an accumulation or a deficiency.
1.1
Diseases linked to an accumulation: “Intoxication” disorders
Historically, the disorders in this group are the most typical IEM and are characterised by signs and symptoms resulting primarily from the abnormal accumulation of the compound(s) proximal to the block and potentially reverse as soon as the accumulation is removed. They share some characteristics:
-
They do not interfere with embryo and foetal development and present after a symptom-free interval with clinical signs of intoxication (acute, intermittent, chronic and even progressive) provoked by intercurrent events and food intake.
-
Most of these disorders are treatable.
-
This group encompasses IEM of amino acid (AA) catabolism (PKU or MSUD), urea cycle defects, organic acidurias (MMA, GA1 etc.), carbohydrate intoxications metals accumulation and porphyrias (Saudubray and García-Cazorla
2018). Some purines/pyrimidines and metabolite repair defects (D/L-2-OH-glutaric, NADPH etc.) could be also included in this group.
In the brain, molecules that accumulate in intoxication disorders can behave as neurotransmitters (Kölker
2018) in the case of amino acids or stimulate biological pathways related to impaired autophagy and nerve growth factors. Synaptic plasticity and excitability are almost constantly impaired and executive functions are especially vulnerable. Therefore, and in spite of proper metabolic control, most of these patients display behavioural, emotional and learning difficulties.
1.2
Diseases linked to a deficiency
Symptoms result primarily from the defective synthesis of compounds distal to the block or from the defective transport of an essential molecule through intestinal epithelium, blood-brain barrier (Table
1 and Fig.
S2 in supplemental material), and cytoplasmic or organelle membranes. Unlike those defects belonging to the intoxication group most of these defects interfere with embryofoetal development causing a neurodevelopmental disruption, have a congenital presentation and share many characteristics with disorders in the complex molecules group (see later). Molecular mechanisms of IEM linked to essential compounds are different from those linked to non-essential ones.
Table 1
Diseases of transport across the blood-brain-barrier. Mechanisms and symptoms
Glucose | Facilitated diffusion | GLUT-1 defect GLUT-10 (not glucose transport but a similar substance) | Epilepsy, ID, abnormal movements Arterial tortuosity syndrome, strokes |
Lactate, ketone bodies | Diffusional, saturable cotransport with protons | MCT-1 defect | Episodes of severe ketoacidosis in early childhood |
Amino acids | Large neutral aa transporter (L-system) Na+ dependent aa transport | BCAA defect (gene SLC7a5) Serine transport defect (gene SLC6a14) | ID, autism, epilepsy, microcephaly, develop delay, hypomyelination |
Lipids | | DHA transporter defect (gene Mfsd2a) | Microcephaly, brain malformation, early death |
Essential compounds come from diet and must be transported through cellular membranes. Accordingly, IEM are linked to carrier defects (essential amino acids like
SLC 7A5 for BCAA (Tărlungeanu et al.
2016), or essential fatty acids (FA) such as
MFSD2A for DHA (Guemez-Gamboa et al.
2015). BCDH kinase deficiency overactivates, causing irreversible BCAA oxidation in very low levels of BCAA as in
SLC 7A5 mutations and presents a similarly devastating neurological syndrome with neurodevelopmental disruption (Novarino et al.
2013).
Non-essential compounds can be synthesised inside cells. Their availability depends on the integrity of the synthesis pathway. IEM are linked to enzyme defects (such as serine, glutamine, and asparagine synthetase deficiency) (Häberle et al.
2005; Acuna-Hidalgo et al.
2015; Ruzzo et al.
2013). In addition to AA and FA synthesis and transport defects, this group also encompasses the IEM causing metal deficiency (Boycott et al.
2015; Park et al.
2015) as well as neurotransmitter metabolism and transport defects (Tristán-Noguero and García-Cazorla
2018, this issue). Some vitamin-related disorders and purine and pyrimidine defects also belong to this category.
Major neurodevelopmental disruptions lead to severe global encephalopathies where almost all neurological functions are chronically altered. In early onset presentations, patients display severe psychomotor delays affecting both motor and cognitive milestones. Microcephaly and hypomyelination are very common as epilepsy and movement disorders. These defects mimic early “non-metabolic” genetic encephalopathies that affect crucial neurodevelopmental functions such as neuronal precursor proliferation, migration, pruning and dendrite development. This is because these small molecules contribute to antenatal brain “construction” in terms of signalling, cytoskeleton guidance, synapse formation and later on in experience-dependent synapse remodelling.
These consist of IEM with symptoms due, at least in part, to a deficiency in energy production or utilisation within the liver, myocardium, muscle, brain and other tissues.
2.1
Membrane carriers of energetic molecules (glucose: GLUT, FA, ketone bodies, monocarboxylic acids: MCT) display many tissue specific isozymes as GLUT-1 and MCT-1.
2.2
Mitochondrial defects encompass aerobic glucose oxidation defects presenting with congenital lactic acidemias (pyruvate transporter, pyruvate carboxylase, pyruvate dehydrogenase system and Krebs cycle defects), mitochondrial respiratory chain disorders, mitochondrial transporters of energetic and other indispensable molecules,, coenzyme Q biosynthesis, FA oxidation and ketone body defects. A large and growing group of already > 110 disorders involves mitochondrial machinery (Frazier et al.
2017).
2.3
Cytoplasmic energy defects include glycolysis, glycogen metabolism, gluconeogenesis, hyperinsulinism, creatine metabolism disorders and finally inborn errors of the pentose phosphate pathways.
The brain accounts for 20% of an adult’s energy expenditure at rest and more than 50% in a child (Sokoloff
1960). Neurons expend 70–80% of total energy (the remaining portion used by glia) and the great majority (80%) is utilised to fuel neuronal channels. We could then hypothesise that energy defects in the brain tend to behave as “synaptopathies”, thereby encompassing those symptoms within the spectrum of synaptic disorders (Tristán-Noguero and García-Cazorla
2018, this issue).
Energy compartmentalisation between neurons (lactate use, pentose pathway, oxidative phosphorylation) and glia (mostly glycolytic), and even inside different compartments of a single neuron, has been now largely described (Oyarzábal and Marín-Valencia
n.d., this issue; Camandola and Mattson
2017). Fuel molecules such as ATP and lactate also have signalling roles promoting synaptic plasticity. Energy use for axonal transport and nerve conduction is also compartmentalised. Electrically active axons not only rely on glycolysis but also need the supply of lactate provided by oligodendrocytes (that surround axons covering them with myelin) (Trevisiol et al.
2017). Glucose is the obligatory fuel for adult brain, but lactate produced from glucose by astrocytes within brain during activation has been proposed to serve as neuronal fuel. This simple and seductive hypothesis is far from being proven (Dienel
2017). Whatever the source of ATP may be, ATP consumption is greatly increased in demyelinated axons due to the redistribution of ion channels along the length of the denuded axon (Alizadeh et al.
2015; Salzer
2015) and decreasing mitochondrial ATP production results in free radical production leading to lipid peroxidation and severe physico-chemical modifications of cellular and organelle membranes (Dobretsov et al.
1977).
Given the vulnerability of energy homeostasis in the brain, most neurological disorders, and in particular, neurodegenerative diseases are necessarily linked to disturbances in energy metabolism.
This expanding group encompasses diseases that disturb the metabolism of complex molecules that are not or poorly water soluble or diffusible. In general, these defects have no easily identified metabolic markers and diagnosis is primarily based on molecular techniques (NGS, WES). The main chemical categories of such complex molecules encompass the glycogen, the sphingolipids, the phospholipids, the cholesterol and bile acids, the glycosaminoglycans, oligosaccharides and glycolipids and the nucleic acids. Like the small molecules, there are two subcategories in complex molecule disorders defined by whether the phenotype primarily results from an accumulation or a deficiency.
These complex metabolic processes involve all organelles (mitochondria, lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, lipid droplets and the synaptic vesicle) and are highly regulated. Cellular membranes are formed from a chemically diverse set of lipids present in various amounts and proportions. Membrane lipids fulfil many functions including membrane structural components, energy and heat sources, signalling molecules, protein recruitment platforms and substrates for post-translational protein–lipid modification (Harayama and Riezman
2018). There are two subcategories in complex molecule disorders defined by whether the phenotype primarily results from an accumulation or a deficiency.
3.1
Accumulation are linked to catabolism defects leading to storage of a visible accumulated compound (classical lysosome defects like sphingolipidoses or mucopolysaccharidoses) in which signs and symptoms primarily result from the abnormal accumulation of compound(s) proximal to the block and potentially reverse as soon as the accumulation is removed.
3.2
Deficiency are linked to synthesis and remodelling of these complex molecules. They share some characteristics with the vast new group of processing, trafficking and quality control disorders that involve also protein metabolism. They may interfere with embryo and foetal development with neurodevelopmental disruptions, have a congenital presentation and present as birth defects. Symptoms are permanent, progressive, and independent of intercurrent events. This rapidly expanding group encompasses classic organelle disorders (lysosome and peroxisome defects), carbohydrate-deficient glycoprotein (CDG) syndromes and the synthesis defects of all kind of complex molecules biochemical categories.
All defects affecting systems involved in intracellular vesiculation, trafficking, processing of complex molecules and quality control processes (like protein folding and autophagy) recently discovered using the NGS technique belong to this category (Sprecher et al.
2005) (Hirst et al.
2015) (Stockler et al.
2014). This is also the case with the synaptic vesicle (SV) cycle (Cortès-Saladelafont et al.
2018, this issue) and congenital disorders of autophagy like SENDA or Vici syndrome (Ebrahimi-Fakhari et al.
2016).
The neurological manifestations are diverse, complex, with a predominance of motor symptoms (such as spastic paraparesis, ataxia and movement disorders), are often progressive and may be associated with extra-neurological signs. Trafficking, autophagy and quality control processes are major issues in regard to neurochemical mechanisms. These diseases are leading the way to a new neurology that connects metabolism, neuroscience and clinical neurology.
4)
Finally nucleic acid disorders are much more than the classic purine and pyrimidine defects when we include cytoplasmic and mitochondrial tRNA synthetases defects, (Wallen and Antonellis
2013; Smits et al.
2010); ribosomopathies (Mills and Green
2017); diseases affecting mechanisms of DNA/RNA damage reparation and those involved in DNA methylation (DNAm) such as in CHARGE and Kabuki syndromes (Butcher et al.
2017).