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Niemann-Pick Type C disease

Someone I know asked me to see if I could draw any connections between Niemann-Pick Type C disease (abbreviated NPC) and Poison/"Vitamin A".  This is considered a rare genetic disease, so I went into the literature as I do, seeing if there were connections to be made.  Modern medicine has little to nothing to offer those suffering from this issue.

From the National Organization of Rare Disorders, some background:

Niemann-Pick Type C

General Discussion

Summary

Niemann-Pick disease type C (NPC) is a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. The accumulation of these substances damages the affected areas. NPC is highly variable and the age of onset and specific symptoms can vary from one person to another, sometimes even among members of the same family. NPC can range from a fatal disorder within the first few months after birth (neonatal period) to a late onset, chronic progressive disorder that remains undiagnosed well into adulthood. Most cases are detected during childhood and progress to cause life-threatening complications by the second or third decade of life. NPC is caused by mutations in the NPC1 gene (NPC type 1C) or the NPC2 gene (NPC type 2C) and is inherited in an autosomal recessive manner.

Introduction

NPC belongs to a larger group of more than 50 disorders known as lysosomal storage disorders. Lysosomes are membrane-bound compartments within cells. They contain enzymes that break down large molecules such as proteins, carbohydrates and fats into their building blocks. Abnormal functioning of a transport protein leads to the accumulation of cholesterol and other fatty substances in various tissues of the body, including brain tissue. 

So, we have a connection to *lysosomal* disorders.  Problems with the lysosomes.  We're going to use that.

Also, remember the "accumulation of cholesterol and other fatty substances [aka lipids] in various tissues in the body".  You'll see this come up again.

Are there any obvious connections in the literature to Poison/"Vitamin A" (aka hypervitaminosis A) to causing lysosomal-related (lysosome) problems?  Yes, there are!

Hypervitaminosis A and Lysosomes

1. Introduction
Increased emphasis on the beneficial effects of ingestion of retinoids and other vitamins has led to a growing practice of self-medication, over-prescription and over-consumption of these nutrients by a significant portion of the world's population (Baurenfeind 1980, McLaren 1981, Farris and Erdman 1982).

Note that these warnings were coming out 40 YEARS AGO.

Some changes at the subcellular level due to high amounts of vitamin A are known. For example, in liver the structure of the Golgi apparatus is altered (Morre et al. 1981), lipids accumulate (Moore 1967), and mitochondria swell (Moore 1967).

Lipid accumulation, right there.

Additionally, excess retinol in vitro causes erythrocytes to expand markedly (Dingle and Lucy 1962), mitochondria to swell (Lucy et al. 1963, Keiser et al. 1964), and lysosomes to rupture (Lucy and Dingle 1964). Because of the centrol role of lysosomes in pathology (de Duve et al. 1962), effects on this organelle have attracted considerable attention as possibly being involved in hypervitaminosis A toxicity.

Lysosome rupture caused by retinol Poison/"Vitamin A".

Note the "central role of lysosomes in pathology [...] as possible being involved in hypervitaminosis A toxicity."

Lipid accumulation is mentioned.  Recall from above that cholesterol deposits are also an associated problem of NPC.  Is there any evidence of Poison/"Vitamin A" retinoids causing cholesterol deposits in the body?  Yes.

Pathophysiology

Xanthomas are cholesterol-rich depositions that can appear anywhere in the body during various disease states. XP is a type of xanthoma that occurs over the eyelids, with the absence of xanthomas elsewhere. Xanthomas can be associated with primary hyperlipidemias, such as types II and IV, having low high-density lipoprotein (HDL) levels, or secondary hyperlipidemias, such as hypothyroidism, diabetes mellitus, drugs5 (glucocorticoids, cyclosporine, cimetidine, estrogens, some antihypertensive medications, retinoids, certain antiepileptic drugs, anabolic steroids, tamoxifen, etc.), and food (diets rich in saturated fats, cholesterol, and alcohol). XP can occur in normolipidemic persons with low HDL levels.

Cholesterol-rich deposits--called xanthomas--anywhere in the body in various "disease states" can be associated with Poison/"Vitamin A" retinoid medications.  More on that topic:

Xanthomas are localized lipid deposits within organs that may manifest as papules, plaques, or nodules in skin. The clinical variants of cutaneous xanthomas include a wide arrange of lesions such as cutaneous xanthomas that can be idiopathic or may present as a sign of an inherited abnormality of lipoprotein metabolism (primary dyslipidemia), hyperlipidemia secondary to systemic disease or medication, or hematologic disease.
[...]
Examples of medications that may lead to hyperlipidemia (often hypertriglyceridemia) include estrogens, tamoxifen, prednisone, oral retinoids, cyclosporine, olanzapine, and protease inhibitors [11-14].
[...]
Often, the classic yellow or yellow-red color and distribution of eruptive, tuberous, and plane xanthomas (eg, eyelids in xanthelasma) enables a presumptive diagnosis.

Important things to note:
  • Xanthomas in the organs (likely including the brain) may or may not be reflected as xanthomas on the skin.
  • Retinoid medications linked here yet again.
  • The carotenoid colors are yellow, red, and orange (yellow + red).  Note how these are the "classic" colors of xanthomas.  Coincidence?  Hardly.

There is more on Poison/"Vitamin A" causing lysosome problems.

Lysosomes and Joint Disease

Immune reactions can result in the labilization of lysosomes. Weiss and Fell19 have shown that heterologous antibodies to mouse tissues produce changes in organ cultures of cartilage which closely resemble those brought about by the lysosomal effects of hypervitaminosis A.
[...]
The effect of hypervitaminosis A in promoting release of cartilage-degrading protease from lysosomes both in vivo and in vitro has been extensively reviewed5, 12 and is mentioned here only as another example of the capacity of lysosomal labilizers to bring about tissue destruction.

Apparently any excess of Poison/"Vitamin A" is very bad for the lysosomes and their PROPER function in the body.

Next, are there any treatments for NPC and do they have any connection to Poison/"Vitamin A" toxicity.  Yes!  It's called cyclodextrin.

First, how it is studied and used for NPC:

Collaborative development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease

There are no therapies for Niemann-Pick disease type C1 approved by the Food and Drug Administration (FDA), but 2-hydroxypropyl-ß-cyclodextrin (HPBCD) appears to reduce the cholesterol and lipid accumulation and prolongs survival in disease animal models.

FDA Approves First Ever Cyclodextrin Infusion Treatment For Twin Girls Suffering From Fatal Cholesterol Disease

From what we understand, this will be the second time in the United States that cyclodextrin alone has been used in an attempt treat a fatal disease. Over 20 years ago, cyclodextrin was used in a medical case involving a boy with severe hypervitaminosis A and cyclodextrin saved the child’s life. In Addi and Cassi’s case, we are trying to save the girls from Niemann Pick Type C disease, a fatal cholesterol metabolism disorder that is often referred to as the “Childhood Alzheimer’s.”  There is no cure for NPC and only one experimental drug treatment.

I like the above article because it ties cyclodextrin to treating both NPC and hypervitaminosis A.  Are you seeing the connections yet?

"Childhood Alzheimer's". Interesting.  Here is my gigantic article where I show quite conclusively (in my opinion) that the foundation of Alzheimer's Disease is in Poison/"Vitamin A" toxicity. Are the childhood versions and the adult versions caused by the same thing?  I believe so.

More on cyclodextrin being used to treat hypervitaminosis A:

Rescue from hypervitaminosis A or potentiation of retinoid toxicity by different modes of cyclodextrin administration.

A synthetic derivative of beta-cyclodextrin in which all 2, 6 hydroxy groups were converted to methoxy groups (dimethyl-BCD), considerably accelerated the dissolution and increased the solubility of all-trans retinoic acid. Dimethyl-BCD affected the toxicity of retinoic acid in mice in a manner depending on the method of administration: (a) when dimethyl-BCD was administered simultaneously with retinoic acid, the toxic effects were increased and set in rapidly without symptoms of hypervitaminosis A, (b) when dimethyl-BCD was administered alone, after the hypervitaminosis A had been established, the survival rate was improved.

Severe hypervitaminosis A in siblings: Evidence of variable tolerance to retinol intake

A 2-year-old boy had signs and symptoms of chronic hypervitaminosis A. A course of increasing severity led to eventual death. A younger brother later had similar clinical features. Chicken liver spread containing up to 420 IU/g vitamin A was the likely source of intoxication.

I have used this research elsewhere on this blog-forum.  I would like it to be emphasized, one more time, for the people who need to see and hear it again.  This child was poisoned to death from the Poison/"Vitamin A" in CHICKEN LIVER SPREAD.  The other boys in the family were being poisoned by it as well!  So much for those internet-know-nothings who say that "Vitamin A from liver (or by extension, cod liver oil) can't possibly be toxic."  Please stop listening to their unfounded, unscientific lies.

Markedly elevated circulating retinyl ester levels have persisted in the surviving sibling for 3 subsequent years despite severe restriction of vitamin A intake.

Correcting Poison/"Vitamin A" toxicity is not a weekend cleanse.  As I have been saying more recently, it is a process that is measured in months and even years.

A therapeutic trial of the carbohydrate-derived complexing agent 2-hydroxypropyl-beta-cyclodextrin was initiated. Circulating retinyl esters transiently increased during the infusion (from 407 to 4791 micrograms/dL), and urinary total vitamin A excretion, undetectable before infusion, increased to 23 micrograms/dL after infusion.

This increased mobilization of Poison/"Vitamin A" from the liver into the blood (increase in circulating retinyl esters), which then increased the Poison/"Vitamin A" that was able to be excreted by the kidneys into the urine (increase in urinary total Vitamin A excretion).  Basic detox stuff.

The frequency of hypervitaminotic episodes has decreased somewhat in the 2 years since the infusion, probably related to dietary vitamin A restriction.

The most important thing in the process of recovering one's health from Poison/"Vitamin A" toxicity is the consistent drastic reduction and minimization (it cannot be completely avoided, nor is that necessary for recovery) of Poison/"Vitamin A" from the diet.

Note that the researchers talk about how the boys were doing this for three years...and that there was NO detectable Vitamin A in their urine.  Something these boys were doing (or was done to them) was shutting down the renal/kidney route of Poison/"Vitamin A" detoxification, hence why they stayed toxic for so long!  This is likely a nutrient problem, and is thoroughly addressed in the Poison/"Vitamin A" and Glyphosate Detox Program.

The occurrence of this syndrome in two brothers, while a sister ingesting the same diet remains completely healthy, suggests an inherited variance in tolerance to vitamin A intake.

The question of: "Why does this YouTube or liver/dairy/cod-liver-oil pushing pseudocelebrity get to eat these things all the time and he doesn't get sick?"  It is explained above, and also by survivor bias.  This does not mean that they are not developing problems from it, it simply means that the problems aren't obvious yet. Ever seen someone you thought was quite healthy on the outside suddenly keel over from a heart attack or suddenly be diagnosed with a quite serious cancer?  A book cannot be judged by its cover. Note that NPC is a genetic disease...could it simply be a genetic propensity towards earlier and greater damage from Poison/"Vitamin A" toxicity?  I'd say that is quite possible.

One of the ways I look to see if Poison/"Vitamin A" is behind a problem is to see if nutrients known to be protective against or depleted by Poison/"Vitamin A" are associated in the literature with the condition.  It would seem that Vitamin E deficiency is related to both NPC and Poison/"Vitamin A" toxicity.

Altered vitamin E status in Niemann-Pick type C disease

Taken together, our observations indicate that functionality of NPC1/2 proteins is necessary for proper bioavailability of vitamin E and that the NPC pathology might involve tissue-specific perturbations of vitamin E status.
[...]
It is interesting to note that common pathological and biochemical hallmarks are shared by NPC disease and deficiency in the dietary antioxidant vitamin E. First, in both cases, the major site of dysfunction is the central nervous system (CNS), and the major clinical presentation is cerebellar ataxia (2325), accompanied by specific injury to cerebellar Purkinje neurons (2627). Second, axonal spheroids (focal swellings) are frequently observed in both NPC disease (28) and in vitamin E deficiency (2931).

Vitamin E is depleted by Poison/"Vitamin A", see here for the research.

Similarly, pronounced hypomyelination is characteristic of advanced-stage disease in both cases (3233). Finally, modest supplementation with vitamin E has been reported to result in a mild improvement in motor performance in a mouse model of NPC disease (34).

Vitamin E is protective against Poison/"Vitamin A" damage, see here for the research. Note that Vitamin E supplementation ("modest", and probably not a great type either) has been shown to help in a mouse model!

"Tissue-specific perturbations" sounds a lot like the "tissue-specific antibodies" that show up in another Poison/"Vitamin A"-caused condition, that being autoimmunity.

As another link to Niemann-Pick Disease Types A and also B, which involve problems with the sphingomyelinase enzyme. Below, we see that sphingomyelinase is dependent upon magnesium, and that I've already shown that Poison/"Vitamin A" depletes magnesium.

Magnesium-dependent sphingomyelinase of infantile brain. Effect of detergents and a heat-stable factor.

The properties of the Mg2+-dependent sphingomyelinase, whose pH optimum is between 7 and 8, were investigated using post-mortem infantile brain.

Niemann-Pick diseases in general affect infants and children the most, particularly their brains.
Sphingomyelinase, the main enzyme involved in Types A and B, is DEPENDENT upon MAGNESIUM, notably in the BRAIN of INFANTS.
Poison/"Vitamin A" depletes magnesium.
Just more "coincidental" connections.

Let's make another connection.  Fibrillin-1.

 

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