(I meant to type oculocerebrorenal in the title, but my mind isn't working especially well this week, due to the intranasal flu vaccine.) This article [Ramanathan et al., 2009: (http://www.sajaa.co.za/index.php/sajaa/article/viewPDFInterstitial/387/428)] is maybe a poorly-chosen example of an article about Lowe syndrome [the "oculocerebrorenal syndrome of Lowe" (OCRL)], but there are plenty of articles on it (http://scholar.google.com/scholar?q=oculocerebrorenal+Lowe&hl=en). On the surface, the manifestations of OCRL look very similar to Fanconi's syndrome and to the manifestations of intracellular phosphate depletion, but, apparently, many people who have OCRL, caused by hypofunctionality of the OCRL protein(s), or who have a subtype of Dent's disease that is caused by mutations in the OCRL protein (the OCRL protein is an inositol polyphosphate 5-phosphatase that hydrolyzes mainly phosphatidylinositol 4,5-bisphosphate, or PtdIns(4,5)P2, into phosphatidylinositol 4-phosphate but also hydrolyzes other phosphatidylinositols, including phosphatidylinositol 3,4,5-triphosphate, or PtdIns(3,4,5)P3, into phosphatidylinositol 4,5-bisphosphate, etc.) do not display the phosphaturia or hypophosphatemia and rickets that characterize X-linked hypophosphatemic rickets and that occur or can occur in Fanconi's syndrome [Kleta, 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18667737)]. But there's still a lot of overlap with the manifestations of intracellular phosphate depletion and with Fancon's syndrome and other causes of hypophosphatemia. There's hypercalciuria, proteinuria, hypercalciuria, etc., and the proximal tubules are relatively selectively affected, in terms of the effects of the disorder on the kidneys. OCRL also causes vacuolar changes in myelin that fall short of overt demyelination, and OCRL causes cataracts and glaucoma, etc. The encephalopathy and mental retardation in OCRL is seemingly more severe than the effects of hypophosphatemia, but I've cited articles in past postings showing that rather devastating central nervous system damage can result from hypophosphatemia. It's conceivable that intracellular phosphate depletion in neurons and astrocytes, in parts of the brain, is more common than is recognized and that the depletion of phosphate does, in fact, commonly cause vacuolar myelopathy (which, incidentally, is not a very specific neuropathological change and occurs in a variety of contexts, including vitamin B12 depletion, etc.). It's not all *that* generic, as a neuropathological manifestation, however, and OCRL is still similar to Fanconi's syndrome, in my opinion and the opinion of others [Erdmann et al., 2008: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2025683)(http://www.ncbi.nlm.nih.gov/pubmed/17765681)]. It's not really useful to say that it's a totally different condition, when there's so much overlap of the manifestations.
My first thought was that the mutations in OCRL were causing intracellular phosphate depletion with something like intermittent hypophosphatemia, but the most direct manifestation of OCRL (the syndrome) is the aberrant accumulation of PtdIns(4,5)P2, primarily. One possibility is that, in humans who display significant intracellular phosphate depletion and develop proximal tubular acidosis and other changes that overlap with those found in OCRL or Dent's disease caused by mutations in the OCRL protein (Dent's disease can also result from mutations in chloride transporters), there's a generalized depletion of different phosphatidylinositols that, by some mechanism, leads to a similar skewing of the abundances of different phosphatidylinositols in favor of PtdIns(4,5)P2, as in OCRL. Or it's possible that, in OCRL, the impairment in the hydrolysis of PtdIns(4,5)P2 leads to a reduction in the availability of inorganic phosphate for use in ATP formation, much as the sequestration of phosphate in fructose 2,6-bisphosphate can cause ATP depletion following a fructose load. Or, maybe the formation or turnover of mutiple PtdIns's are upregulated in a way that sequesters inorganic phosphate, in multiple pools of PtdIns's, in a way that's maladaptive and detrimental to energy metabolism. Or, it may have nothing to do with energy metabolism.
But Erdmann et al. (2008) found, basically, that the accumulation of PtdIns(4,5)P2 in endocytic vesicles apparently deranged the trafficking of megalin to the apical membranes of proximal tubule epithelial cells. In any case, there can be abnormalities in the uptake of calcium and other constituents of tubular fluid and in receptor-mediated endocytosis by megalin in response to the conditions that occur in people who have OCRL mutations (and the OCRL syndrome) (Erdmann et al., 2008). Erdmann et al. (2008) mention that deranged megalin signalling could account for the CNS abnormalities and that patients with Dent's disease (even the forms due to mutations in chloride transporters) exhibit abnormalities in the functioning of megalin. Erdmann et al. (2008) didn't mention it, but megalin transports vitamin B12 bound to transcobalamin (http://scholar.google.com/scholar?hl=en&q=transcobalamin+megalin) and also transports vitamin D bound to vitamin D binding protein (http://scholar.google.com/scholar?hl=en&q=%22vitamin+D+binding+protein%22+megalin). Megalin serves a transport function across the blood-brain and blood-CSF barriers (http://scholar.google.com/scholar?hl=en&q=megalin+%22blood-brain%22+OR+%22blood-CSF%22), and the "spongy" changes in myelin or "pallor" of myelin (http://scholar.google.com/scholar?hl=en&q=myelin+OCRL+pallor+OR+spongy) seen in people who have OCRL hypofunctionality are reminiscent, in my mind, of the vacuolar myelopathy seen in subacute combined degeneration, due to vitamin B12 depletion (http://scholar.google.com/scholar?hl=en&q=vacuolar+myelopathy+B12), or in humans who have methionine adenosyltransferase deficiency, etc. [(http://scholar.google.com/scholar?hl=en&q=vacuolar+myelopathy+methionine+OR+%22S-adenosylmethionine%22+OR+%22S-adenosyl-L-methionine%22); (http://scholar.google.com/scholar?hl=en&q=myelin+deficiency+%22methionine+adenosyltransferase%22)].
It's interesting that cycloleucine, an inhibitor of methionine adenosyltransferase (MAT), the enzyme that synthesizes S-adenosylmethionine (SAM-e), causes "vacuolation" of myelin (http://scholar.google.com/scholar?hl=en&q=myelin+cycloleucine+vacuolation+OR+vacuolar). It's likely that "vacuolar myelopathy," which can sometimes be characterized by pathological changes in the myelin and also in oligodendrocytes or other cells [such as inclusion bodies in the nuclei of different cell types (http://scholar.google.com/scholar?hl=en&q=%22vacuolar+myelopathy%22+inclusion+body+vacuolation+OR+vacuolar)], is heterogeneous, but one interpretation would be to say that phosphate depletion can reduce SAM-e levels by reducing ATP and adenosine nucleotide pools in oligodendrocytes and other cell types. ATP depletion is known to be capable of causing SAM-e depletion [see either Morrison et al., 1997, or Eto et al., 2002, both of whom showed that SAM-e levels were decreased in the brains of people who had had Alzheimer's disease (the authors in at least one group were saying, correctly, in my view, that the SAM-e depletion was really likely to have been caused by ATP depletion): (http://scholar.google.com/scholar?hl=en&q=ATP+%22severely+decreased%22+Alzheimer%27s+%22S-adenosylmethionine%22)], and that, together with derangements in the abundance of PtdIns(4,5)P2 and other phosphatidylinositols (causing reduced vitamin B12 transport into the brain by reducing the megalin-mediated uptake of B12, etc.), could account for the web of associations I've discussed in this article. It's interesting that Reed et al. (2007) [Reed et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17392004)] found that cats that displayed low serum vitamin B12 and low serum folate levels also tended to display low serum phosphate levels (Reed et al., 2007). One could attribute that to any number of changes and say that the cats had some kind of Fanconi's syndrome that impaired reabsorption of folate binding protein, transcobalamin, and also inorganic phosphate from the tubular fluid. It's known that megalin knockout mice display low-molecular weight proteinuria (http://scholar.google.com/scholar?hl=en&q=megalin+proteinuria), as discussed by Erdmann et al. (2008), and lose different vitamins and other proteins in their urine, and megalin also transports folate binding protein (http://scholar.google.com/scholar?hl=en&q=megalin+folate+binding+protein). But phosphate depletion per se can cause metabolic acidosis or ATP depletion without acidosis in the proximal tubules and could, in my opinion, be a cause and consequence of proximal tubule pathologies. Here's another article that describes an association of B12 depletion with phosphate depletion and that could be explained by the fact that malabsorption, as in liver disease, can cause hypophosphatemia and cobalamin deficiency and also folate depletion [Wojtyczka, 1998: (http://cs.portlandpress.com/cs/095/0735/cs0950735.htm)(http://www.ncbi.nlm.nih.gov/pubmed/9831699)]. Those types of effects, such as loss of vitamin B12 and reduced folates and phosphate in the urine, could explain some of the post-infectious mono issues that people have [(http://scholar.google.com/scholar?hl=en&q=infectious+mono+nephritis+OR+tubular+OR+tubulointerstitial+OR+%22proximal+tubule%22); (http://scholar.google.com/scholar?hl=en&q=infectious+mono+adverse+OR+complication)]. It could be similar to the research showing that cerebral folate deficiency can result from expansion of the pools of antibodies that bind to the reduced folate carrier and other folate transporters at the blood-CSF barrier, given that the immune infiltration of the EBV-infected proximal tubule epithelial cells (http://scholar.google.com/scholar?hl=en&q=infectious+mono+EBV+%22proximal+tubule%22) could create a mess of immune-mediated impairments in proximal tubule functioning (such as by cytokine-mediated disturbances in energy metabolism, etc.). Supposedly, EBV doesn't infect choroid plexus epithelial cells, but I wouldn't be surprised if it did (http://scholar.google.com/scholar?hl=en&q=EBV+%22choroid+plexus%22). There are some significant problems with the notions that a lot of people have about the cell types that EBV supposedly can or can't infect. Here are some more searches [(http://scholar.google.com/scholar?hl=en&q=%22choroid+plexus%22+CD21+OR+C3d+OR+C3R); (http://scholar.google.com/scholar?hl=en&q=EBV+C3R+OR+C3d+OR+CD21)]. Everyone assumes that CD21 isn't likely to be expressed by cells in the CNS and that EBV must infect cells by binding to CD21, but what if it isn't true. A lot of viruses can infect cells using multiple transport mechanisms, some of which have only recently been discovered for influenza, for example. Also, there are significant problems with detecting EBV proteins during autopsies, and many articles look for EBV DNA or viremia (there's not going to be a bunch of viral DNA floating around, all over the place, in a cell latently-infected with EBV). EBV infects epithelial cells in basically every other organ, and it probably infects astrocytes and microglia (http://scholar.google.com/scholar?hl=en&q=EBV+infection+astrocyte+OR+%22human+monocytes%22) and pericytes (http://scholar.google.com/scholar?hl=en&q=resident+macrophage+pericyte+brain) and fibroblasts (i.e. meningeal fibroblasts, probably) [see Koide et al., 1997: (http://scholar.google.com/scholar?hl=en&q=EBV+fibroblasts)]. That type of effect on the proximal tubules could reduce phosphate and vitamin D and reduced folate and vitamin B12 reabsorption by the kidneys and could produce similar impairments at the blood-CSF barrier, etc. (http://scholar.google.com/scholar?hl=en&q=infectious+mono+brain+complication+OR+adverse).
I don't claim to be able to explain all of the different manifestations of these conditions, but the overlap of the effects of OCRL mutations with the effects of idiopathic Fanconi's syndrome and also the effects of intracellular phosphate depletion are fairly difficult to ignore completely. There must be some explanation, but it's interesting, in any case.
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