Fragile X Friday: Folic Acid

Our Story….



Back in August when Holly was 6 months old we visited the UC Davis MIND Institute and saw Dr. Randi Hagerman. This would have been our third visit and the completion of the Minocycline one month study. We discussed what our options were for moving forward, next steps after the completion of the Minocycline. It was recommended that we wait 1-2 months before doing anything just to make sure there was no skill regression after stopping the Minocycline, and then begin a High Dose Folic Acid treatment. At the time we were seeing Dr. Hagerman under her Research Grant, and she was not able to do any prescribing, but provided me the documentation I would need to have my Pediatrician write the prescription.

The dosage is High, compared to other protocols my pediatrician was used to, and it was not easy to get a liquid preparation, we ended up having to go to Children’s Hospital and the only liquid form they had was the fluid used for IV Administration, it can in several small little IV glass jars and needles that were used to poke the jar and get the liquid out. Insurance did not cover an injectable, and it was not inexpensive, and well to be honest the administration was rather strange and intimidating.

At the time I was quitting my job and we were changing to inferior insurance, and with the reduction in income I wasn’t sure I wanted to buy all of the syringes and IV Vials every month, so we ended up putting of the treatment.

Then I spoke with Sarah over at Love & Survival, and found out Quinn had taken Folic Acid. It was only for a month, and they stopped, but she told me they were able to get a liquid bottle from Elephant Pharmacy that was a fluid not unlike Baby Tylenol and was very easy to administer. Her dosage for a much older and larger boy was much smaller then that recommended for Holly so we again were encouraged and decided to wait yet again, to make sure that Dr. Hagerman Really wanted the high dosage.



Then I read a post from Umma over at Basically FX explaining that Monkey had been on Folic Acid for 4 months and she was very happy with the results. She advised that she was told it takes at least 3-4 months to see a response. So I was glad I had waited, because I would have stopped after 1 month and no response.

Armed with this new information we went for another visit to UC Davis and saw Dr. Hagerman again. Our pediatrician came with us to get a tour of the center, meet Louise and Randi in person, and get all the information she could.

We discussed the new dosage protocol, as Holly was much bigger now, and Dr. Hagerman advised that her Pharmacy will mix up a solution and it was a 3 month supply for only about 20$ She said that I would need to go to a compounding pharmacy locally to refill, but they could call her pharmacy for the recipe. This was encouraging, and so finally 6 months after the fact we finally started.

Folic Acid was much easier to administer compared to the Minocycline as it could be taken with Milk or Formula. It is required that Holly take a supplement with B6, so we are also now giving her a Multivitamin with iron, Vitamin D, and B6 among a few other good things. I give this to her every day in a 6 ounce bottle of Formula right before her morning nap, and it has been about 2 weeks so far.

So I guess in about 10-14 more weeks you will get an update from me on whether or not we think that the Folic Acid has made a difference. From what I have read it is supposed to help with attention and hyperactivity. Holly is a very active girl, she does jump from one thing to another, perhaps it is her environment, I give her so much to play with it is easy to get distracted and bounce around, but she has a stimulated activity and at times she is able to focus on a single toy and play, so maybe this will help.


I am not sure how it works either, it is one of those things that is like, it can’t really hurt you so why not try it and see if it helps, and “maybe” a Fragile X brain doesn’t know how to use the Folic Acid it has, or it has too little, so more helps, but there is no hard and fast proof. But you know what, I am all for try it, and see if it helps. So let’s see.

Here is the technical information below on Folic Acid that might help inform you on the details.

The Research:

Folic Acid

Folic acid was the first medication reported to be beneficial for individuals with FXS (Lejeune 1982). When added to tissue culture media, folate will decrease cytogenetic expression of the fragile site (Jacky 1996). However, its mechanism of action in the central nervous system seems to be unrelated to its cytogenetic effect. In the CNS folate is involved with methylation and hydroxylation, and both reactions are important in neurotransmitter synthesis and metabolism (Greenblatt et al. 1994). Folate is concentrated in the synaptic regions of CNS neurons (McClain et al. 1975). Levine et al. (1981) speculated that exogenous folate may accelerate dopamine synthesis in nigrostriatal neurons through effects on tyrosine hydroxylase. Preliminary reports from Lejeune (1982) and others (Harpey 1982; Lacassie et al. 1984; Lejeune et al. 1984) anecdotally demonstrated improvement in behavior and development in males with FXS treated with folic acid. Subsequent controlled studies showed mixed results, with some reporting no benefit from folic acid (Rosenblatt et al. 1985; Brown et al. 1986; Froster-Iskenius et al. 1986; Madison et al. 1986; Fisch et al. 1988), whereas others demonstrated improvement with folic acid treatment (Carpenter et al. 1983; Brown et al. 1984; Gustavson et al. 1985; Gillberg et al. 1986; Hagerman et al. 1986; for review see Aman and Kern 1990; Turk 1992; and Greenblatt et al. 1994).

Folic Acid: Response

Clearly, not all patients with FXS respond to folic acid, but a significant number of prepubertal boys with FXS are reported by their families to be less hyperactive and to have a better attention span on folate. The cognitive improvements in young boys with FXS reported by Hagerman et al. (1986) seem to be the result of improvement in attention span and concentration, which is consistent with the hypothesized effect on dopamine synthesis (Levine et al. 1981). The effect of folic acid is similar to the response noted with stimulant medication, although the latter usually causes a more dramatic improvement in attention. A rare patient will become more hyperactive on folate, and an occasional adult with FXS will have more outbursts on folate. It is, therefore, not recommended for adult patients, who are less frequently plagued by hyperactivity.

Improvements in speech, language, and motor coordination are also occasionally reported by parents when their children are taking folic acid (Hagerman et al. 1986; Turk 1992). The effectiveness of folic acid has been difficult to document in controlled studies; if a child responds to folate, however, parents usually insist on using it. As many parents are adamant about its effectiveness, perhaps future studies should focus on identifying the subgroup of children with FXS who respond. There is no evidence for a metabolic defect in folate metabolism in FXS (Brondum-Nielsen et al. 1983; Wang and Erbe 1984). There is one report of a child with FXS who deteriorated behaviorally and developmentally after treatment with trimethoprim, an antibiotic that interferes with the metabolism of folic acid (Hecht and Glover 1983). Therefore, caution should be used in treating patients with FXS with drugs that lower folate levels, including phenytoin.

Folic Acid: Side Effects

Folate has been tolerated without significant side effects in dosages as high as 250 mg and 1,000 mg/day (Zettner et al. 1981; Brown et al. 1986). However, Hunter et al. (1970) reported malaise, sleep problems, irritability, and an increased activity level when folate was given to normal, healthy volunteers. Folate has been reported to exacerbate the frequency of seizures in epilepsy (Reynolds 1967), but we have not experienced this problem in patients with FXS and seizures. Folate treatment should be avoided, however, in patients with poorly controlled seizures. Folate may occasionally cause loose stools and can prolong diarrhea in children recovering from gastroenteritis. If diarrhea occurs, the dose of folate should be lowered or discontinued until the diarrhea resolves. We reported vitamin B6 deficiency in males with FXS taking 10 mg of folic acid per day (Hagerman et al. 1986). To avoid this problem, patients should take daily a multiple vitamin with B6 while on folic acid therapy. Folate can also interfere with zinc absorption in the intestine, and serum zinc levels should therefore be monitored at least once a year (Milne et al. 1984).

Folic Acid: Liquid Preparation

Folic acid is manufactured only in 1-mg tablets in the United States. A liquid preparation of 5 mg/ml is more convenient and less expensive than the tablet form. Most patients who respond will demonstrate improvement on a dose of 10-50 mg/day. Many pharmacies will prepare the liquid preparation after a special request. Pharmacies can obtain folic acid powder U.S.P. through Tanabe U.S.A., Inc., 7930 Conroy Ct., San Diego, California 92111 (1-619-571-8410) or Mike Jones at Gallipot (1-800-423-6967). The following formula can be used to mix the folic acid solution to a dilution of 5 mg/ml (provided by Rob Rodgers, Pharm.D., at The Children's Hospital in Denver, Colo.): 10 g folic acid, 2,000 ml H2O (sterile), 15 ml NaOH 20%--add by titration until mixture clarifies in solution. Folic acid solution is sensitive to heat and photodegradation, and it must be refrigerated and protected from light in a covered or brown bottle. A syringe can be used to measure a typical dose of 5 mg or 1 ml twice a day. As folic acid is relatively tasteless, it can be squirted directly in the mouth or added to juice. The dose is usually given twice a day to avoid stomach irritation or diarrhea, which occasionally occurs.

Folic Acid: Medical Follow-up

The medical follow-up of patients treated with high-dose folic acid includes a periodic physical and neurologic examination and at least annual blood work including a complete blood count (CBC): serum glutamic-oxaloacetic transaminase (SGOT); blood urea nitrogen (BUN); creatinine; urine analysis; and serum levels of zinc, vitamin B6, and folate. A trial of folic acid therapy should last at least three months because improvements in behavior or attention may not begin until the second month. If folate is helpful, it should be continued, and it can be used together with stimulant medication. At least once every one to two years, the folic acid can be discontinued to assess whether it remains effective. There is some evidence to suggest a mild withdrawal effect in a limited number of patients, characterized by mood lability lasting one to two weeks. This is not uncommon in megavitamin therapy, and it has been described in pyridoxine and ascorbic acid therapy (American Psychiatric Association 1973; Gualtieri et al. 1987).

http://www.nfxf.org/html/folate.htm

http://www.fragilex.org/html/liquid.htm

This article is not intended to give medical advice for individual cases. Any change in medical treatment should be done in consultation with appropriate medical personnel. This article is written for medical professionals. Some of the terms will be unfamiliar to those who are not trained in medical fields.*This article is from the chapter on treatment in the 3rd edition of Fragile X Syndrome: Diagnosis, Treatment, and Research edited by Randi Jenssen Hagerman, M.D. and Paul Hagerman, M.D., Ph.D., to be published May 2002. It is included with permission from The Johns Hopkins University Press. References to other chapters refer to chapters in the book which are not included as part of this website.The complete 3rd edition of Fragile X Syndrome: Diagnosis, Treatment, and Research can be ordered from the National Fragile X Foundation by calling 1-800-688-8765 or from The Johns Hopkins University Press at 1-800-537-5487.

http://www.ucdmc.ucdavis.edu/mindinstitute/ourteam/faculty_staff/rhagerman.html