Ramaekers found that compared with healthy children, the level of 5- methyltetrahydrofolate in cerebrospinal fluid of these children was very low, but the concentration of 5- methyltetrahydrofolate in their blood was normal. Because the concentration of 5- methyltetrahydrofolate in cerebrospinal fluid can represent the level of folic acid in the whole brain, he named this neurodevelopmental disorder cerebral folic acid deficiency syndrome.
Before we know more, let's take a look at what the blood-brain barrier is.
/kloc-At the end of 0/9, paul ehrlich, the great god who invented the first chemical drug arsenic Fanmina 606, found that if he injected aniline dye into animals, all organs of the poor creature would be dyed purple, except the brain tissue. When the Great God slaps his head, he must be a stupid human animal. His brain is full of water and brain cells, and he forgot this phenomenon before he sucked enough aniline. A few years later, Edwin Goldmann, his student, had a whim and injected aniline directly into the spinal cord of animals, only to find that the world was upside down: the brain tissue of animals was stained, but other organs of the body were not. In fact, this phenomenon observed by ehrlich and Goldman is the first evidence of the existence of blood-brain barrier.
Due to the existence of the blood-brain barrier, all kinds of components in the blood, except basic small molecules such as oxygen, carbon dioxide and blood sugar, other molecules, including dye molecules in Ehrlich's body, various drug molecules and, of course, macromolecules such as protein, cannot freely enter the brain through the blood-brain barrier. If you want to enter, these molecules need some special means, that is, to get the help of various transporters on brain capillary endothelial cells.
You can imagine this process like this: you want to meet the leader, who is so busy that he doesn't even know where the next minute is. What shall we do? Find his secretary! As long as the secretary is willing to help you, you can not only meet the leader, but also have two drinks with the leader to deepen your feelings. These transporters are the "secretaries" of the blood-brain barrier.
Folic acid is an essential vitamin in the brain, so there is a "secretary" on the blood-brain barrier, called folic acid receptor, whose job is to identify folic acid in the blood, and then wrap folic acid and transport it to the cerebrospinal fluid side of the blood-brain barrier. Whether this folic acid receptor works well or not determines whether there is enough folic acid in cerebrospinal fluid.
Because the level of folic acid in the blood of patients with cerebral folic acid deficiency syndrome is normal, and the level of folic acid in cerebrospinal fluid is low, it is obvious that the folic acid receptor did not fulfill its responsibility and did not carry enough folic acid into the brain. In the hot era of gene sequencing, Lamex also followed suit and thought: Did these patients have a mutation in the folate receptor gene, which made the folate receptor weak and sick and unable to perform their duties?
However, to his great disappointment, none of the patients had a problem with the folate receptor gene! To his disappointment, such a big discovery can only be published in the little-known academic journal Developmental Medicine &; Child neurology. Of course, this last sentence is the villain's heart of Broccoli Jun.
Learn from a painful experience, what is pain! Raemacker worked hard in seclusion for two years.
This time, he examined the serum samples of 28 children diagnosed with cerebral folate deficiency syndrome, 28 healthy children of the same age and 465,438+0 patients with other nervous system diseases. As a result, he found that as many as 25 of the 28 patients had antibodies against folate receptors in their sera. On the contrary, none of the sera of 28 healthy children had this receptor! 4 1 None of the patients with other nervous system diseases has this receptor in their serum!
Open the dark clouds and see the light of day. Now Ramaekers understands that folate receptors are not trying their best, not because they are lazy or sick, but because they are blinded by folate receptor antibodies! These folate receptor antibodies bind to the folate receptor so tightly that the folate receptor has no chance to contact the folate surface at all. . . It's like a secretary is sugarcoated by the bourgeoisie and addicted to close contact with beautiful women every day. Where does he have time to listen to your nonsense?
If we stop here, we will underestimate Comrade Lamex. He gave full play to the great teaching that it is advisable to chase the poor bandits with the only courage left, not to take the overlord as a teacher, and to win and attack them. Now that we know what it is and why, of course, we should also know how to do it otherwise-only asking questions without solving them is very likely to be regarded as hooligans.
Since the brain lacks folic acid, make it up!
But wait a minute, now that the folic acid receptor comrades are so corrupt that they can't be used, can they still supplement folic acid? Shouldn't we save the comrades with folic acid receptors first?
Actually, it is not.
It turns out that there is also a comrade who can transport folic acid on the blood-brain barrier called reduced folic acid carrier. Compared with the folate receptor, this comrade, who is a carrier of folic acid reduction, eats a lot and refuses to do anything until he is full-his binding force with folic acid is relatively low, only one thousandth of that of the folate receptor, and he is unwilling to work at the normal serum folate level. However, as long as you are willing to spend money to substantially increase the serum folic acid level, in principle, reducing folic acid carriers can also provoke the revolutionary task. So the comrades of folic acid receptor should be corroded by it.
Six months after Comrade Ramaekers supplemented high-dose folic acid/folinic acid to 28 patients, the folic acid level in patients' cerebrospinal fluid really rose from the average of 20.6 before treatment (82 in healthy group) to 73.3, and many symptoms were improved or even greatly improved: all patients' syncope/epilepsy symptoms were obviously improved, and 865,438+0% patients' dysphoria and sleep disorder symptoms were improved. The symptoms of dyskinesia and cerebellar ataxia were improved in 85% patients, the symptoms of head growth retardation were improved in 84% patients, and the symptoms of mental retardation or autism were improved in 40% patients.
In particular, of these 28 patients, 4 were diagnosed with autism. The level of folate receptor antibody in three serum samples was particularly high, but no folate receptor antibody was detected in the remaining 1 serum samples. After a large dose of folic acid supplementation, although the treatment effect of two older patients (5 years old and 12 years old) was quite poor, the communication ability and abnormal symptoms of nervous system of two younger patients (2 years old and 3 years old) improved well, and the 3-year-old patient who did not detect folate receptor antibody actually recovered completely and entered ordinary schools.
Having done so much, Comrade Lamex has been richly rewarded this time. The paper was accepted and published by the first medical journal "New England Journal of Medicine", and he officially became the originator of cerebral folic acid deficiency syndrome.
With the pioneers, it is much easier for the latecomers to follow up.
Taking autism as an example, a follow-up study found that about 75% of autistic children contain one folate receptor antibody, and about 25% of autistic children contain two folate receptor antibodies at the same time. Another study confirmed this finding: 60% of autistic children contain folate receptor antibodies. At the same time, based on this discovery, the researchers also carried out a number of clinical studies on high-dose folic acid supplementation for autism, which showed certain therapeutic effects, especially for patients with folate receptor antibodies detected in serum. Therefore, if an autistic person is diagnosed with cerebral folic acid deficiency syndrome, then a large dose of folic acid supplementation is likely to have a good therapeutic effect.
As for how the body can run out of a folate receptor antibody, Comrade Ramaekers holds that: 1) Dairy products, including breast milk, contain a folate binding protein; 2) The baby's intestine is not fully developed, and some folic acid binding proteins eaten have not been completely degraded and quietly infiltrated into the body; 3) The immune system found these "intruders", so it made folate-binding protein antibodies; 4) Unfortunately, this folate binding protein is very similar to the folate receptor (9 1% amino acid sequence is the same), and the original antibody against folate binding protein can also attack its own folate receptor. In short, it is the price of the revolution, which accidentally injured friendly forces!
Therefore, Comrade Ramaekers specifically pointed out that it is best to strictly avoid dairy products when treating cerebral folic acid deficiency syndrome.
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