Cerebral Folate Deficiency – The biggest puzzle piece yet

I have always had a lot of unanswered questions.  There were a lot of pieces to the puzzle that didn’t seem to make sense until I learned about Cerebral Folate Deficiency and its association with autism.

Cerebral Folate Deficiency (CFD) is a relatively newly identified disorder in which there is low 5MTHF (5-methyltetrahydrofolate) in the CSF (cerebrospinal fluid) but normal 5-MTHF in the blood.  5-MTHF is the bioavailable form of folate.   Folic acid is the synthetic form of folate and supplementing with it can often makes problems worse and not better.  These kids need the bioavailable form of folate.  When there is not enough, developmental delays can occur.  Symptoms can manifest as irritability, poor sleep, gross motor problems, seizures and developmental delay among other symptoms.  It often shows itself in young children and regression is typical.  Often, but not always, these kids have a smaller head circumference and CFD is linked to mitochondrial dysfunction in a subset of children.   Cow’s milk down regulates folate receptor autoantibodies (FRAs), so going dairy free is very important.  Folate receptor autoantibodies (FRAs) block the transport of folate into the Cerebral Spinal Fluid and they are being found at an alarming rate in children with autism.  FRAs, dairy and mitochondrial dysfunction are not the only way that CFD occurs.   There are a number of genetic mutations that affect folate metabolism. 

I also discovered that the mothers of these children often cannot break down folic acid themselves due to genetic reasons.  There are several gene mutations that can lead to this problem.  MTHFR is only one of them.  The mother’s shortage of folinic acid sets up their baby for problems in the womb.  Another noteworthy piece of information is that birth control pills deplete the body of folinic acid, putting young mothers-to-be at a strict disadvantage.

**Please note that taking folic acid, as young pregnant mothers-to-be are advised, DOES NOT help.  In fact, it may make problems worse because these mothers cannot break down folic acid, which is the synthetic form of folate.   Instead these pregnant moms should be taking folinic acid or L-5MTHF.   A few prenatals have now started using the good forms of folate in their prenatals.  Thorne is one such company.

Folate is needed to support the metabolism of purines and pyrimidines which are the building blocks of RNA and DNA.  They also are also very important for cells to make energy properly.  If you are diagnosed with CFD, Leucovorin, a high dose folinic acid, is prescribed because it is a versatile form of folate.

The more I read, the more alarmed I became.  Everything I read was hitting home in a very scary way.  There were so many red flags in both my & my baby’s history.  First I will address what was concerning about my history.

I had trouble getting pregnant for a year after stopping birth control pills.  Finally, I got pregnant at age 28 and I was extremely sick during pregnancy.  I was hospitalized several times and vomited a minimum of 10 times per day until my body gave in and my water broke at 33 weeks old.  She had a grade 4 IVH (Intraventricular hemorrhage) at birth.  Not enough folate could explain this occurrence.

Following my first pregnancy with Marley, I had a miscarriage and then an ectopic pregnancy that ruptured.   Both of these could be attributed to not enough folate.

Then I got pregnant with my second child, Skylar, and at the advice of an applied kinesiologist, I started taking L-5MTHF (the broken down form of folate with a methyl donor attached for better absorption) and I was not as sick.  And the baby did much better!!  I did go into premature labor with her at 34 weeks but she held on until 39 weeks.  Perhaps I was not taking enough L-5MTHF?

When I got pregnant with my third baby, I again took methylfolate (800mcg), felt better but had lots of contractions.  I went into premature labor with him at 29 weeks and was put on best rest until he came at 39 weeks.  He is developmentally fine but has severe food allergies.  Again, Perhaps I was not taking enough L-5MTHF?

More things that are concerning about my folate metabolism: 

I have elevated MCH & MVH, which are indicators of either not enough folate or not enough B12. 

I am FOLR2  +/+ (which will block folate receptors)

I am DHFR  +/- (which converts dihydrofolate into tetrahydrofolate)

I am SLC19A1  +/- (which is a transporter of folate and is involved in the regulation of intracellular concentrations of folate.)

As for my daughter, there is even more reason for concern and more red flags:

As I noted before, my daughter had had a grade 4 IVH (Intraventricular hemorrhage) at birth.  She also has a syrinx in her spinal cord that likely developed in utero as well.  Not enough folate could explain these problems. 

She also has strabismus, which may be attributed to her brain bleed OR it could be attributed to a Cerebral Folate Deficiency.

Marley was an irritable baby and she didn’t sleep well at all.  She slept through the night for the first time at 18 months old, but it still was not consistent….a few days on and several days off.  All red flags for CFD.

At age 3, we started her on L-5MTHF (800mcg) and by the next day, she could walk down steps independently.  She was also having hours long screaming tantruming sessions, which ended with staring spells which we believed to be absent seizures.   They stopped when we started the L-5MTHF.  She has been on L-5MTHF ever since.

When she was age 30 months, the genetics department pointed out that she had an unusually small head and therefore, was a good candidate for Rett’s disease, for which they tested her.  The test came back negative along with a completely normal microarray.  Around this time, she was diagnosed with severe, low-functioning autism.  Low-functioning, regressive autism is a sign of CFD.

Marley also has genetic markers that indicate problems with folate metabolism:

She is FOLR1  +/- (which will block folate receptors)

She is FOLR2  +/- (which will block folate receptors)

She is DHFR r +/- (which converts dihydrofolate into tetrahydrofolate)

She is MTHFR A1298C +/- (which converts 5-MTHF to THF)

She is SLC19A1 +/+ (which is a transporter of folate and is involved in the regulation of intracellular concentrations of folate.)

Add all this to the fact that she fatigues easily, has chronic constipation, has tight muscles on her left side, is still developmentally delayed and has problems with focus and I was concerned.   If she did have CFD, she may start to have seizures once puberty hit.

Since this is a fairly new diagnosis and few mainstream pediatric neurologists know about CFD being tied to Autism, I had to ask around to see what doctor would be my best bet with whom to approach with all this information.  We have seen several neurologists in the past and they have had nothing to offer us at all…..so I wanted to make this appointment count.

If it turned out that she has Cerebral Folate deficiency, she would be prescribed Leucovorin, which is high dose calcium-folinic acid in an effort to bring up her levels of L-5MTHF in her CSF.

I was in luck.  I live in a city with great medical resources and a fabulous, well-known hospital and there just happens to be a pediatric neurologist on staff that knows about and understands CFD and it’s link to Autism.  I made an appointment.

I don’t have much luck with doctors, but to my surprise and pleasure, he was both wonderful and knowledgeable…….and concerned.  He agreed with all the information I presented to him and said he wanted to do a lumbar puncture right away to rule CFD in or out.  He said to me:

"Kids with autism should have a full neurological and metabolic work-up to see if there is something we can do. Autism is a set of symptoms and if we can find something treatable to help with their symptoms we should do it."

Yes....after taking Marley to see several neurologists and developmental peds over the years who have tried to send us out the door with an antidepressant or an anti-psychotic drug, or GI docs that I had to beg to help my daughter when she was in terrible, excruciating pain.....that afternoon I hit the jackpot.

He listened. He was interested in what I had done to take her this far in her development. He said "if we can find something that is treatable, many of my patients go on to be extraordinary adults. Not just ordinary....but extraordinary because not only are they functioning independently but they have extra gifts to share."

And the appointment was made for a lumbar puncture.

I was terrified.

We went into the hospital early in the morning.  They used Versed & Fentanyl to sedate her, but she is hard to sedate and even with the maximum dosage of both sedatives, she sang to them during the procedure.  

Recovery was hard.  She was in extreme pain for 2 days.  She was dizzy and couldn’t stand.  We had her lie flat on her back & pushed fluids like crazy to get her body to reproduce more spinal fluid to relieve the pressure.  By the 3^rd day, she had excruciating headaches that were relieved only when she laid flat on her back.  I was panicked.  But the neurologist told me that it can take some kids a week to recover and to keep pushing fluids and keep her flat on her back.  I did and by day 5, things were looking up.  She was up and around for about 30 minutes before the headaches set in.   By day 6, there were less symptoms.  By day 9 she was recovered from the lumbar puncture and the waiting game for results began.

We were on vacation when I got the call from the pediatric neuro resident who had done her lumbar puncture.  She said ….

“We have about half of Marley’s results in and everything is normal.”

I was shocked.  I said “Define normal.  Tell me her numbers.”

She told me Marley’s 5-MTHF is a 44 (range 40-120).  I exclaimed, “THAT’S NOT NORMAL! That is very low!  It is HALF of what it should be.  We want her to be between 78-82.  Especially considering she has been dairy free and supplemented with 5-MTHF almost all her life! Look at the study published in 2013 by Dr Frye and Dr Rossingol showing that kids with autism have levels anywhere from low 40’s to 80’s and that combined with FRA’s (Folate receptor autoantibodies) puts them at a huge disadvantage.  See the levels of the kids treated here. They treated these kids with Leucovorin and the kids showed gains in several areas.  See the study here.

The pediatric resident just told me to take my argument to the attending doctor whom we had met originally. I did….and after hearing my argument, he agreed with me that she needed to be treated for Cerebral Folate Deficiency.  I think he is still learning about all of this because I had to tell him the dosage of Leucovorin that is used to treat CFD and he easily agreed with me after trying to prescribe a much lower dose.  The neurologist said to look for increased socialization, less emotional meltdowns, more tolerance to foods (less picky eating) and better gross motor skills with Leucovorin.

All of this information is in the study and in current literature on CFD and Autism Spectrum Disorders and it left me wondering why pediatric neurologists are left in the dark on this subject.    This is a huge break-through in Autism.  And it is TREATABLE!  If caught and treated early enough, Leucovorin can provide significant progress or even a complete recovery of both neurological and ASD symptoms.

In the 2013 study, 93 children were studied for Folate Receptor autoantibodies and they were found in 75% of the children.  FRAs are only one cause of Cerebral Folate Deficiency. From the abstract:  “Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD.”

There is only one lab that can measure FRAs in blood and they have recently reopened. However, the ONLY way to test for CFD is with a lumbar puncture.

A great paper on Cerebral Folate Deficiency and Autism 

It has become clear to me that our local pediatric neurologist does not know enough about CFD to treat my daughter appropriately, so I have made an appointment with one of the doctors that actually wrote the study.  He will see her in a few months.  I hope to have her on Leucovorin very soon and report to him how she is doing.  I also know that bringing up 5-MTHF levels in the CSF is a slow process, so I don’t expect over-night results.  Instead I need to look for slow and steady gains. 

I am so hopeful for her future and I will keep you posted on her progress.   

Thank you for your love and support while she continues to heal.

 For even more information on Folate and its association with Autism, click here.