A Review on the Molecular Causes of Epilepsy

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• PMC4409128

Nat Neurosci. Author manuscript; available in PMC 2016 Mar i.

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PMCID: PMC4409128

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Molecular mechanisms of epilepsy

Abstract

Decades of experimental work take established an imbalance of excitation and inhibition equally the leading mechanism of the transition from normal brain function to seizure. In epilepsy, these transitions are rare and abrupt. Transition processes incorporating positive feedback, such as activity-dependent disinhibition, could provide these unique timing features. A rapidly expanding array of genetic etiologies will help delineate the molecular machinery(due south). This depiction will entail quite a bit of prison cell biological science. The genes discovered to appointment are currently more than remarkable for their diversity than their similarities.

Introduction

Epileptic activeness can be induced acutely by blocking synaptic and voltage-gated inhibitory conductances^{1, 2}, or by activating synaptic and voltage-gated excitatory conductances³. Seizures are blocked past the contrary manipulations: increasing inhibition⁴ or decreasing excitation⁵. Several decades of these types of pharmacological experiments take established the idea that an imbalance between inhibitory and excitatory conductances leads to seizures (i.e. is ictogenic) in otherwise normal encephalon tissue⁶. This imbalance is most clearly embodied clinically in toxic exposures such as domoic acid, which activates excitatory GluK1 glutamate receptors, or past overdoses of theophylline, which blocks the inhibitory adenosine A1 receptor^{7, 8}. In these cases, immediate, repeated, and medically intractable seizure action is induced in otherwise normal subjects. An imbalance between excitation and inhibition is thus a validated ictogenic mechanism. Difficulties arise in extending this mechanism to epileptogenesis, that is, equally a mechanism that creates a persistent increase in the probability of spontaneous seizures.

Chronic epilepsy rather than toxic exposure is responsible for the vast majority of seizures in man patients, and this condition requires an expansion of the theory of an imbalance between inhibitory and excitatory conductances. This expansion is needed for two reasons. Showtime, unlike the acute exposures, the timing of seizures in chronic epilepsy is unpredictable and seizures are relatively rare, representing much less than 1 % of the total brain activity except in the almost severe epileptic encephalopathies^nine. Thus in chronic epilepsy, not just is an ictogenic machinery required, but this mechanism or an additional mechanism must too explain the timing of episodic transitions from normal activeness to seizures.

The 2d surface area of difficulty in applying a theory of imbalanced inhibition and excitation is that the etiology of epilepsy does non usually suggest such an imbalance. In epilepsies arising from a genetic cause, analyses of the genetic etiology accept occasionally found causal loss-of-functions mutations in inhibitory conductances^x, simply loss-of-function mutations are also found in several excitatory conductances^{11, 12}, and the majority of causal mutations involve loss of function of genes that practise not directly modify the remainder of inhibition and excitation^thirteen. Commercially available diagnostic genetic sequencing services at present feature panels of several hundred genes that have been associated with epilepsy. About of these genes exercise not encode membrane conductances. This is in line with the intermittent nature of seizures described in a higher place; genetic abnormalities that compromise important inhibitory conductances would be expected to continuously alter brain function. Thus such mutations are most frequently associated with severe epileptic encephalopathies, in which there are no normal epochs of brain activity, and frequent seizures^{fourteen, 15, 16}.

In the acquired epilepsies, spontaneous seizures brainstorm later on injury to a normal brain as a consequence of trauma, stroke, infection or status epilepticus. Steady-country imbalances in excitation vs. inhibition are difficult to demonstrate in established animal models of acquired epilepsy. Damage to inhibitory neurons is compensated by increases in GABAergic synaptogenesis before the onset of seizures in the pilocarpine model¹⁷. Compensatory glutamatergic synaptogenesis also occurs¹⁸, but steady-land network imbalances in excitation vs. inhibition are not apparent in experimental and human epilepsy¹⁹.

Thus we need to expand the experimentally-derived idea of fourth dimension-invariant ictogenic imbalances between inhibition and excitation to encompass both the timing of seizures and the broad variety of etiologies of human epilepsy.

Timing of seizures

I explanation for the timing of seizures in chronic epilepsy is an episodic shift in the balance of inhibition and excitation, which begs the question as to the mechanisms of the episodic shifts in this balance. Other possibilities include seizure mechanisms that are of low probability, for instance circular or reentrant activity that can occur simply in network states that exist very rarely. The probability of entry into a seizure under such weather condition may not exist a straight consequence of the molecular mechanism of ictogenesis. For example, in autosomal dominant nocturnal frontal lobe epilepsy (ADFNLE) arising from gain-of-function mutations in a nicotinic cholinergic receptor, seizures only occur in not rapid middle movement (nonREM) slumber^xx (Ferini-Strambi et al. 2012). Thus network (brain) states may exist an of import determinant of seizure timing. Network states that are less probable than nonREM slumber may exist responsible for proportionately lower frequencies of seizures: for example, in catamenial epilepsy, seizures occur predominantly at specific stages of the menstrual bike²¹. While global brain states may help explain changes in seizure probability, they do not directly explain seizure timing. For both ADFNLE and catamenial epilepsy, most of the at-hazard periods are characterized by the absence of seizure activity. Thus in the loftier-risk periods, additional mechanisms must induce farther, ictogenic alterations of the rest of inhibition and excitation.

Unpredictable and low-frequency events tin can be readily generated by low-probability state transitions in nonlinear systems^{22, 23}. While this trunk of analysis does non lend itself to elucidating molecular mechanisms, it does emphasize that the improbable land itself must be at to the lowest degree temporarily stable. If the ictal land were non stable, there would exist continual exits at random times from the seizure state, which generally does not occur: both experimental and human seizure durations are stereotyped, ranging from seconds for absence epilepsy to one or two minutes for chief and secondarily generalized tonic clonic seizures.

One way to explain both low-probability ictal transitions and ictal stability is to incorporate positive feedback into the ictogenic mechanism (Figure). For example, if transient imbalances in inhibition and excitation engendered farther imbalance, this imbalance could occasionally build to the indicate of engendering a seizure. Activeness-dependent reductions in the efficacy of neuronal inhibition, or activeness-dependent disinhibition, comprises ane such mechanism, or prepare of mechanisms^{24, 25, 26}. If disinhibition occurred only at extremes of local network activeness, so the probability of ictal transition would depend on the probability of that exceptional level of local network activity. Presumably these levels of activity could occur over the same range of probabilities as those characterizing spontaneous seizures. Once a seizure was induced by an activity-dependent reduction in the residuum of inhibition to excitation, the seizure itself could continue to produce activity levels that were sufficient to suppress inhibition or enhance excitation, providing the necessary positive feedback to sustain the seizure.

Episodic surges in network activity may rarely cross a "seizure threshold" of activeness level at which positive feedback mechanisms such as activity-dependent disinhibition boss network dynamics. The variances of the summed inputs to the epileptic network is proportional to the sum of the input variances, leading to rare surges of the intensity of input. In the case of activeness-dependent disinhibition, levels of input above this seizure threshold rapidly degrade inhibition in the epileptic network, leading to further increases network activity. This process culiminates in a seizure.

Molecular mechanisms of activity-dependent shifts in the residue of inhibition and excitation

One manner to delimit candidate ictogenic mechanisms is to consider the duration of the epochs of elevated network activity that lead to seizures. Some candidate mechanisms can be excluded if nosotros assume that the ictogenic mechanism must operate on the fourth dimension scale relevant to the epoch of increased activity. Unfortunately, we don't really know how long these high-activity epochs might be. Clues include induction of seizures in experimental animals undergoing kindling²⁷, and in patients undergoing electroshock handling²⁸; for such subjects, stimuli of a few seconds are sufficient to engender seizures. The duration of these stimuli represents the lower bound of epoch duration, because the applied stimuli synchronously activate many afferents, and such synchrony is unlikely to exist engendered by physiological activity.

On a fourth dimension calibration of seconds, short-term synaptic plasticity could be a relevant machinery of ictogenesis. Potentially ictogenic mechanisms of short-term synaptic plasticity include depression at inhibitory GABAergic synapses onto principal neurons²⁴, and depression of glutamatergic synapses onto inhibitory neurons²⁹, as well as facilitation of glutamatergic synapses between chief cells^thirty, and facilitation of GABAergic inhibitory synapses onto inhibitory interneurons ³¹. In brusk, either depression or facilitation, with loci at either GABAergic or glutamatergic synapses, could be proconvulsant, depending on the blazon of postsynaptic neuron. Neurotransmitter vesicle fusion with the presynaptic membrane requires the coordinate activity of a set of proteins subserving docking, priming, and fusion of the vesicles as well equally calcium entry, sensing, and export ³². Sustained fusion of neurotransmitter vesicles with the presynaptic membrane requires efficient neurotransmitter and vesicle recycling. Mutations in many of these presynaptic proteins have been demonstrated to be associated with epilepsy^{33, 34}, whereas the anticonvulsants pregabalin and levetiracetam interact with presynaptic calcium channels and docking proteins ³⁵. While these findings support the idea that abnormal short-term synaptic plasticity could underlie ictogenesis, it has non yet been demonstrated that abnormal short-term synaptic plasticity is necessary or sufficient to engender seizures or epilepsy ³⁶.

Postsynaptic mechanisms of synaptic plasticity interim on slightly longer time scales that are still likely to be relevant to epochs of increased network activity include include neurotransmitter reuptake, receptor desensitization, receptor membrane trafficking, and post-translational modifications of receptor subunits affecting transmitter analogousness and channel gating. Mutations in proteins subserving some of these functions have been associated with epilepsy. For example epilepsy is engendered by mutations in the gene encoding for the stargazin fellow member of the transmembrane AMPA receptor regulatory protein (TARP) family that modulates many aspects of AMPA-type glutamate receptor subunit membrane trafficking ^{37, 38} likewise as by mutations in genes encoding for the LGI1 / ADAM22 proteins that link stargazin to the mail service synaptic density ³⁹. Some of these mechanisms, such as membrane trafficking of NMDA and GABA_A receptors, accept been implicated in the pathological prolongation of seizure activeness initiated in normal animals by chemic or electrical stimulation ^{40, 41}. Intracellular signaling networks may participate in these activeness-dependent shifts in the balance of excitation and inhibition ^{42, 43}.

Collectively the epileptogenic mutations in pre and postsynaptic proteins support the idea that functional shifts in the residuum of inhibition vs. excitation arising from abnormal synaptic plasticity could transform high-normal levels of network activeness into ictal activeness. Another prominent machinery of activity-dependent disinhibition involves dysregulation of ionic concentrations in the intra and extracellular spaces. Ions that accept been implicated in action-dependent ictogenesis include potassium, calcium, protons, and chloride ^{44, 45, 46, 47}. The relevant proteins involved in ionic homeostasis are broadly distributed in the brain, and include transmembrane channels and transporters in the membranes of the neuronal cytoplasm and subcellular organelles. Mutations in many of the genes encoding these proteins take been associated with epilepsy ^{33, 15, 48}. A dandy deal of experimental work has gone into testing the thought that activity-dependent shifts in ion concentrations contributes to ictogenesis. For instance, tetanic stimulation of afferents every bit well as chemically induced seizure activity results in increases in K⁺ _o equally potassium efflux overwhelms the ability of NaKATPase to maintain the appropriate cation gradients ⁴⁶. The increment in K⁺ _o shifts the potassium reversal potential to depolarized values, so that the resting membrane potential of neurons and cotransport of other ions is compromised. Similarly, large influxes of Ca²⁺ through voltage and ligand-gated conductances overwhelms the capacity for restorative calcium ship, resulting in reductions in extracellular calcium ^{49, fifty}, altering both neurotransmitter release probability and the magnitude of calcium-dependent potassium conductances.

Prolonged activation of inhibitory GABAergic conductances can also dethrone inhibition as a upshot of excitatory shifts in the GABA_A reversal potential. The GABA receptor is permeable to chloride and bicarbonate, although nether near circumstances the higher concentration and permeability of chloride make it the dominant accuse carrier ⁵¹. When high levels of GABAergic synaptic activity are sustained for periods on the society of one second, the chloride flux through the GABA_A receptor channel overwhelms the transport capacity of the cation-chloride cotransporters that maintain the steady-land transmembrane chloride gradients ^{52, 53}. This is due to the finite maximum velocity of the transporters equally well as the finite velocity of NaKATPase, which maintains the appropriate driving forces for the cations whose diffusion provides the free energy for chloride cotransport ⁵⁴. Nether these circumstances, chloride becomes relatively passively distributed, and then that the driving force for net ion movement through the GABA_A aqueduct is largely due to bicarbonate. The bicarbonate slope does not degrade with activity because the gratis improvidence of CO_two across the membrane and subsequent hydration/rehydration via carbonic anhydrase provides a strong buffer for the bicarbonate concentration. Complimentary CO₂ diffusion keeps the bicarbonate approximately symmetrically distributed on both sides of the membrane, so that bicarbonate currents reverse near 0 mV. Thus the shift to net bicarbonate flux causes the GABA conductance to become very strongly depolarizing, so that instead of inhibition, GABAergic circuits subserve excitation as long as the GABA conductance is in excess of cotransport chapters ^{52, 53, 55}.

The activity-dependent synaptic and ionic mechanisms of disinhibition described to a higher place can result in ictal action in normal tissue subject to sufficiently prolonged synchronous input in vivo and in vitro ^{56, 57}. Presumably, normal subjects exercise not experience seizures considering the activeness-dependent changes in synapses and ion concentrations practise not cross the threshold needed to generate a cocky-reinforcing, positive feedback cycle of increased action, disinhibition, and consequent farther increases in activeness. However, after injury a number of changes may brand such cycles more than likely. In the undercut model of post-traumatic epilepsy, NaKATPase levels and cotransport chapters are diminished, rendering ion concentrations less stable ⁵⁸. Loss of function mutations in NaKATpase are associated with epilepsy ⁵⁹ and pharmacological reductions in NaKATPase activity engenders seizure activeness in normal tissue ⁶⁰, supporting the thought that degradations in ionic homeostasis during periods of increased network activeness is a key mechanism of ictogenesis.

Setting the stage for activity-dependent shifts in the I/E balance

If rare, loftier levels of network activity create positive feedback cycles that reduce the balance of inhibition and excitation, why isn't anybody epileptic? Has the preceding word just described the processes underlying the generalization of seizures, rather than ictogenesis? These questions suggest two possibilities: epilepsy may arise from uniquely high levels of network activity, or from unique vulnerabilities to action-dependent shifts in the balance of inhibition to excitation. In the preceding section we focused on unique vulnerabilities to high-normal levels of synaptic activeness. In this section, we consider mechanisms that may lead to uniquely high levels of network activeness.

High, ictogenic levels of network activity could occur more than readily in circuits with abnormal feedback due to cortical dysgenesis or the compensatory rewiring that occurs after brain injury. These circuit alterations are discussed in detail elsewhere in this upshot. Hither we consider the molecular mechanisms that might drive the formation of such an imbalanced excursion. A number of mutations in the PI3K / IGF / mTOR pathway have been reported in association with brain malformations that are strongly associated with epilepsy, including focal cortical dysplasias, the gliotic tubers of tuberous sclerosis, and hemimegalencephaly ^{61, 62}. The mTOR cascade is an important anabolic cellular signaling pathway that is activated by growth factors such as IGF besides as abundance of metabolic substrates. Activation of this pathway may exist a necessary step in the outgrowth of afferent and efferent neural processes ^{63, 64}, and then that over-activation of the mTOR pathway may pb to unnecessary neuronal connectivity and epilepsy. Supporting this hypothesis is the more robust repression of seizure action by mTOR inhibitors early in evolution ^{65, 63} when process outgrowth may exist more active and potentially rate-limited by substrate availability, making synaptogenesis sensitive to anabolic cues, vs. more than pocket-size effects observed in the mature brain in which process outgrowth is much more than express ⁶⁶.

The status of a sufficiently anabolic land is perhaps the nigh basic limitation on the development of synaptic connectivity, which is farther influenced past a broad variety of cues that vary with location, prison cell type, and developmental stage. Accordingly, epileptic circuitry tin can be engendered past a host of defects that touch on neuronal migration ⁶¹, procedure outgrowth ⁶⁷ and synaptic plasticity ^{68, 69, 70}. For example, the protein product of ARX, or aristaless related homeobox gene, is a transcription factor that is an important determinant of neuronal migration. ARX mutations have been associated with failure of interneuron migration to their proper cortical target ⁷¹. If a population of interneurons practise not successfully complete tangential migration to a cortical circuit due to mutations in ARX, it is likely that the cortical circuit will exist chronically mis-inhibited. This is because the populations of interneurons that do successfully innervate this surface area may not exist able to presume all of the duties of the interneurons that didn't attain their target. The successfully migrating neurons may non have the advisable firing backdrop, calcium buffers, or synaptic connectivity to successfully inhibit the network under all circumstances ⁷². Such a network would exist decumbent to disinhibition during peaks of network activity, engendering seizures either in the mis-inhibited circuit itself, or in the downstream synaptic targets of the mis-inhibited circuit. A host of signals regulate interneuron differentiation and migration ⁷³, and mutations in many of these signals are associated with astringent epileptic encephalopathies ¹⁴.

Interneurons may migrate to the right place in time to course the proper connections, but nonetheless be unable to provide the levels of negative feedback necessary to prevent ictogenic levels of network activity. An example of this may be the autosomal dominant SCN1A sodium channel mutations that underlies Dravet syndrome, a serious epileptic encephalopathy of childhood. A leading mechanistic hypothesis is that haploinsufficiency of the SCN1A gene results in lower densities of the Nav1.1 sodium channel, and that the concomitant reduction in sodium currents and action potential firing causes the most significant functional compromise in fast-firing GABAergic basket cells ¹¹. In this scheme, handbasket cell function is sufficient to regulate network action under all but the college range of normal network activeness.

Neuronal homeostasis

There are many epilepsies associated with neuronal loss, either due to brain injury or to degenerative disorders. The strategies that neurons employ to rewire circuits are even less well understood than the strategies used to wire the original circuits during evolution. Neuronal homeostasis refers to the procedure by which neurons regulate their excitability. Thus in conditions that engender excess action, neurons downregulate excitatory conductances and upregulate inhibitory conductances; the reverse is true nether conditions of chronically reduced excitation ⁷⁴. After injury to a brain circuit, these mechanisms would be an important means to foreclose the development of over-active neural networks. Nether most circumstances, this is successful: fifty-fifty subsequently severe brain injury, the bulk of patients practise non develop epilepsy ⁷⁵. I reason that some patients develop epilepsy may be that the mechanisms underlying neuronal homeostasis fail to forbid the evolution of a seizure-prone network ^{76, 58}.

While in that location is substantial empirical data supporting the idea of neuronal homeostasis, the molecular mechanisms are not well understood ⁷⁴. Presumably the wiring and re-wiring of neuronal circuits are governed by neuronal homeostasis. Just as neurons may modify their complement of voltage-gated membrane proteins to maintain firing afterwards deafferentation, the formation and weighting of new synapses later injury to inputs may be driven past like mechanisms. Considering these mechanisms of neuronal homeostasis are unknown, we don't know how, or if, seizures impact neuronal homeostasis. Although ictal activity levels are high, the rarity and brevity of seizures may reduce their impact on the feedback mechanisms governing synaptic homeostasis. For example, a daily seizure lasting 1 minute may be a catastrophe for the patient, but implies an ictal duty cycle of less than 0.1%. The duration of epochs of activity necessary to influence neuronal homeostasis are not known. If the epileptic circuit is significantly deafferented as a consequence of injury or dysgenesis, such that inter-ictal activity is too depression, it may be that the overall activity level of the epileptic circuit (including seizures and epochs of postictal depression) averages to a level that is within the "acceptable" range of the homeostatic mechanisms. Or it may exist that ictal hyperactivity and the characteristic postictal low average to an acceptable level of action, and the processes that regulate neuronal homeostasis average the two periods together. Epilepsy might also arise from defects in the homeostatic mechanisms, for example an inability to assign an appropriately negative weight to synaptic solutions that result in seizures.

Because we don't accept a good thought as to what intracellular signaling networks regulate neuronal action levels, genetic epilepsies may provide our all-time clues equally to what some of the necessary elements of this network might be. Many of the genes whose mutations are linked to epilepsy are involved in intracellular signaling, and thus could be involved in neuronal homeostasis (Ran et al. 2014).

Neuronal homeostasis gone awry

A second approach to deciphering molecular mechanisms of neuronal homeostasis is to consider genes for channels that must exist exquisitely regulated in order to maintain normal neuronal excitability. The concept of neuronal homeostasis was starting time derived by considering the consequences of transient pharmacological derangement of voltage-gated sodium channels and ligand-gated GABA_A channels ⁷⁷. Are there genetic "experiments of nature" that correspond to these ideas? Dravet syndrome was mentioned earlier as an early epileptic encephalopathy resulting from mutations in genes encoding ion channels, near unremarkably SCN1A gene encoding Nav1.1 sodium channels ¹¹ although causal genes may likewise include presynaptic proteins and ligand-gated GABA_A channels ⁷⁸.

Loss of office mutations in sodium channel genes would exist expected to underlie disorders of sensation, movement, and knowledge rather than epilepsy. However, a wide range of loss-of-role mutations in sodium channels upshot in epilepsy. Every bit discussed earlier, a clever proposed pathogenesis is that fast-firing inhibitory interneurons are unduly affected by some of these mutations, and substantial experimental data support this idea ¹¹. However, why loss of a single allele is sufficient to cause disease is not known; at a molecular level, there is no evidence that the truncated protein exerts a ascendant negative event in experimental models ⁷⁹. This raises the possibility that the mutation alters the expression of sodium channels in the cytoplasmic membrane by interference with the feedback mechanism neurons use to sense and conform the sodium current density. There is some prove for such a mechanism, in that sodium currents are elevated in iPSC-derived neurons bearing human sodium channel mutations, although the developmental stage at which currents were measured was all the same very far from mature and the sodium electric current density was much lower than in the mature animal ⁸⁰(Liu et al. 2013). Nonetheless this experiment raises the possibility that haploinsufficiency is not the core trouble, but rather dysregulation of sodium current density that results in college currents at some developmental stages, and lower currents at others. This modulation of intrinsic excitability, along with the circuit alterations discussed before, are key elements of neuronal homeostasis ⁷⁴. It is possible that conscientious consideration of the molecular pathogenesis of epilepsies such as Dravet Syndrome will provide of import clues to the nature of the mechanisms of neuronal homeostasis, as well as the means by which they may be altered in some genetic forms of epilepsy.

The variety of etiologies of epilepsies

At the fourth dimension of the last major review of the molecular mechanisms of epileptogenesis, the number of genes known to cause epilepsy was xiii, and all of these genes coded for ion channels ⁶⁸. This was prior to the era of rapid, inexpensive cistron sequencing, so the predominance of ion channels was in hindsight a function of what genes were being sequenced. Unbiased sequencing and copy number studies take uncovered over 400 genes closely associated with epilepsy ^xiii. Many of these are discussed in the chapter on the genetics of epilepsy. The majority of the mutations associated with epilepsy are not in inhibitory or excitatory ion channels, so the mechanisms by which mutations lead to seizures and epilepsy need to be broadened. It is possible that entirely new mechanisms of epilepsy volition exist discovered as a outcome of investigations into the cell biology of these newly-discovered gene defects. However, it can also be argued that we will find instead a wider variety of means of engendering the core mechanism of episodic, self-reinforcing shifts in the residuum of excitation and inhibition. In this scenario, new genes volition be institute to act, both singly and in concert with other factors, to influence network structure in a way that leads to episodic disinhibition and seizures. For example, there are many factors that make up one's mind the stability of network connectivity, including the survival of neurons, that may be linked to epilepsy. As an example, the intractable epilepsies associated with neurodegenerative diseases ⁸¹ such every bit the neuronal ceroid lipofuscinoses ⁸² can be virtually readily explained as network instabilities engendered by loss of connectivity, including loss of neurons. Thus the molecular mechanisms of the epilepsies may be considered as a diverse set of pathways leading to a concluding common pathophysiology of a self-reinforcing bike of activity-dependent disinhibition.

These genetic "experiments of nature" have provided us with a wide variety of pathways to epilepsy. Where does that exit neuroscientists doing "experiments of the laboratory"? The positive feedback mechanisms that underlie the distinctive timing features of seizures can now be approached by network studies fabricated possible by new technologies in microscopy, action-dependent biomarkers, optogenetics, and computation. The timing of seizures is also ripe for report with improvements in electrode applied science, telemetry, signal assay, and seizure detection. Finally, every gene discovered has a complex cellular biological science that will take some time to unravel. With luck, the large numbers of discovered genetic mutations tin can exist exploited to develop categories of genetic etiologies. Those categories in turn may be very helpful in focusing our pathophysiological investigations. I will not try to gauge those categories at this stage of gene discovery, but I look forward to the point where categorization becomes viable.

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Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409128/

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