alt=diagram explaining pathophysiology of CDAlthough the pathophysiological causes of CD symptoms are still unclear, there are developing theories on the causes of myelination issues, gelatinous cortical white matter and seizures. Issues in Myelination Molecular Water Pump (MWP) and Osmolyte Imbalance Increased cerebrospinal fluid (CSF) pressure and intramyelinic edema in CD patients suggest the existence of an efficient MWP in the brain. The MWP is a membrane protein responsible for pumping water molecules, along with dissolved NAA molecules, from the intraneuronal space to the interstitial space. In healthy individuals, NAA is first transported down the concentration gradient through the MWP from neurons to the interstitial space and subsequently hydrolyzed by AspA in neighbouring oligodendrocytes. In patients with CD, it is theorized that AspA deficiency causes accumulation of NAA in the interstitial space, inducing an osmolyte imbalance and accumulation of water in the interstitial space. This increases hydrostatic pressure between interlamellar spaces and extracellular periaxonal and parenchymatous space, loosening the tight junctions between them, thus causing intramyelinic edema. Subsequent demyelination possibly contributes to vacant spaces in the white matter or<unk>  degeneration. Dysmyelination NAA-derived acetates are involved in the synthesis of fatty acids, which are subsequently incorporated into myelin lipids. It is hypothesized that in CD patients, AspA deficiency reduces NAA-derived acetates, and consequently decreases the synthesis of myelin-associated lipids. This leads to dysmyelination, which promotes the formation vacuoles in interstitial space and<unk>  degeneration. However, it has been shown that<unk>  degeneration is not directly caused by the disrupted synthesis of myelin. Animal models show that myelination may still occur in AspA lacking species, possibly due to parallel pathways for myelination during the initial stages of myelinogenesis. Protein Folding and Stabilization Deficiency of AspA lowers acetyl coenzyme A (CoA) expression in cells, which may be responsible for stabilization and correct folding of proteins. This leads to protein degradation, with a particularly large effect in oligodendrocytes. In animal studies of AspA deficient species, protein degradation in oligodendrocytes has been shown to cause severe loss in myelin proteins. Gelatinous Subcortical White Matter The deficiency in AspA, which is vital in oligodendrocytes to produce NAA derived acetate, leads to a lack of regulation in the genetic structure and expression in these cells. This results in the death of oligodendrocytes, hence induces neuronal injury and the formation of vacuoles in the subcortical matter. These vacuoles contribute to the formation of gelatinous-textured subcortical white matter found in many CD patients. Seizures and Neurodegeneration The pathophysiological causes of seizures and neurodegeneration in CD patients are likely due to oxidative stress generated by NAA accumulation. It is postulated that NAA promotes oxidative stress through promoting reactive oxygen species, as well as reducing non-enzymatic antioxidant defenses. NAA also affects multiple antioxidant enzymes, such as catalase and glutathione peroxidase, impairing the detoxification of hydrogen peroxide. Recent animal studies have shown the chronic oxidative stress may cause dysfunction in mitochondria, rendering the brain more susceptible to epileptic seizures.
Spongy degeneration of the central nervous system
Lesional demyelinations of the central nervous system
Inflammatory demyelinating diseases of the central nervous system
Visual pathway lesions
Neurogenic inflammation
Central nervous system fatigue
Effects of early-life exposures to anesthesia on the brain
Neurodegeneration with brain iron accumulation