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April 2012 Topic

Join us Tuesday, April 10, for an informal discussion about folate disorders, inborn errors of folate metabolism, cerebral folate receptor autoantibodies, autism and mitochondrial dysfunction.

What do we know about disorders of folate and inborn errors of folate?

What do we know about folate polymorphisms and autism?

What new research has recently emerged regarding folate and autism?

How has Leucovorin Calcium been used within the mitochondrial community to treat disorders of folate associated with mitochondrial dysfunction?

What are folate receptor autoantibodies (FRA) and how are testing and treating FRA's potentially helpful in kids with autism?

What's the possible connection between FRA's and mitochondrial dysfunction?

What do we know about disorders of folate and inborn errors of folate?

According to Dr. Rosenblatt and Dr. Watkins from the department of human genetics at McGill University in Canada, five disorders of folate have been well studied and identified thus far. 

  1. hereditary folate malabsorption, caused by mutations in the gene encoding the proton-coupled folate transporter (SLC46A1)
  2. glutamate formiminotransferase deficiency, caused by mutations in the FTCD gene
  3. methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene

4-5.  functional methionine synthase deficiency, either as the result of mutations affecting methionine synthase itself (cblG, caused by mutations in the MTR gene) or affecting the accessory protein methionine synthase reductase (cblE, caused by mutations in the MTRR gene).

And they continue to state that more recently additional inborn errors of folate have been identified. These include:

  1. cerebral folate deficiency, which in a few families is caused by mutations in the FOLR1  gene
  2. dihydrofolate reductase deficiency, caused by mutations in the DHFR gene
  3. deficiency in the trifunctional enzyme containing methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities caused by mutations in the MTHFD1 gene.

J Inherit Metab Dis. 2011 Nov 23. [Epub ahead of print]

Update and new concepts in vitamin responsive disorders of folate transport and metabolism.

Watkins D, Rosenblatt DS.

Source

The Hess B and Diane Finestone Laboratory in Memory of Jacob and Jenny Finestone, and Department of Human Genetics, McGill University Health Centre, 1650 Cedar Avenue, Room L3-319, Montreal, QC, Canada, H3G 1A4, david.watkins@mcgill.ca.

Abstract

Derivatives of folic acid are involved in transfer of one-carbon units in cellular metabolism, playing a role in synthesis of purines and thymidylate and in the remethylation of homocysteine to form methionine. Five inborn errors affecting folate transport and metabolism have been well studied: hereditary folate malabsorption, caused by mutations in the gene encoding the proton-coupled folate transporter (SLC46A1); glutamate formiminotransferase deficiency, caused by mutations in the FTCD gene; methylenetetrahydrofolate reductase deficiency, caused by mutations in the MTHFR gene; and functional methionine synthase deficiency, either as the result of mutations affecting methionine synthase itself (cblG, caused by mutations in the MTR gene) or affecting the accessory protein methionine synthase reductase (cblE, caused by mutations in the MTRR gene). Recently additional inborn errors have been identified. Cerebral folate deficiency is a clinically heterogeneous disorder, which in a few families is caused by mutations in the FOLR1 gene. Dihydrofolate reductase deficiency is characterized by megaloblastic anemia and cerebral folate deficiency, with variable neurological findings. It is caused by mutations in the DHFR gene. Deficiency in the trifunctional enzyme containing methylenetetrahydrofolate dehydrogenase, methenyltetrahydrofolate cyclohydrolase and formyltetrahydrofolate synthetase activities, has been identified in a single patient with megaloblastic anemia, atypical hemolytic uremic syndrome and severe combined immune deficiency. It is caused by mutations in the MTHFD1 gene.

What do we know about folate polymorphisms and autism?

Many doctors in the autism/biomed community use folinic acid supplements as a treatment for autism.  Dr. Jill James et. al stated in 2004 that "Based on the observed MTHFR-related genetic variations in children with ASD, it is reasonable to evaluate dietary supplementation with folinic acid and its cofactors in the methylation cycle, e.g. B vitamins and trimethylglycine (Betaine), for these children. This would be particularly important in the subgroup shown to carry MTHFR polymorphisms."

Many children with autism have MTHFR-related genetic variations and it has been hypothesized that this may play a potential role in ASD symptomology.  In an article published in 2004, Dr. Jill James et al. found that children with diagnosed ASD and MTHFR variants have approximately a 30-50% decrease in enzyme activity.  To read this full article, please visit this link:

http://www.jpands.org/vol9no4/boris.pdf

And again, in July of 2011, Blumkin et al. stated that "MTHFR deficiency was reported as a risk factor for neurodevelopmental disorders such as autism spectrum disorder..." To read more, visit this link:

http://www.ncbi.nlm.nih.gov/pubmed/21490592

What new research has recently emerged regarding folate and autism?

In a recent article published in June of 2011, The Institute for Human Genomics at the University of Miami in Florida published an article in which MTHFD1 was suggested as one of three potential candidate genes contributing to autism risk.  This is an interesting article because it's implicating a different folate gene (other than MTHFR) as a possible contributing risk factor for autistic spectrum disorder.  Recently available MEDnomics nuclear gene testing is revealing MTHFD1 mutations in children with mitochondrial dysfunction and autistic features, but due to the fact that 9% of all people are predicted to be homozygous for this variant, no causal conclusions can be drawn at this time. 

Autism Res. 2011 Jun;4(3):221-7. doi: 10.1002/aur.186. Epub 2011 Feb 28.

A de novo 1.5 Mb microdeletion on chromosome 14q23.2-23.3 in a patient with autism and spherocytosis.

Griswold AJ, Ma D, Sacharow SJ, Robinson JL, Jaworski JM, Wright HH, Abramson RK, Lybaek H, Øyen N, Cuccaro ML, Gilbert JR, Pericak-Vance MA.

Source

John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida 33136, USA.

Abstract

Autism is a neuro-developmental disorder characterized by deficits in social interaction and communication as well as restricted interests or repetitive behaviors. Cytogenetic studies have implicated large chromosomal aberrations in the etiology of approximately 5-7% of autism patients, and the recent advent of array-based techniques allows the exploration of submicroscopic copy number variations (CNVs). We genotyped a 14-year-old boy with autism, spherocytosis and other physical dysmorphia, his parents, and two non-autistic siblings with the Illumina Human 1M Beadchip as part of a study of the molecular genetics of autism and determined copy number variants using the PennCNV algorithm. We identified and validated a de novo 1.5 Mb microdeletion of 14q23.2-23.3 in our autistic patient. This region contains 15 genes, including spectrin beta (SPTB), encoding a cytoskeletal protein previously associated with spherocytosis, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a folate metabolizing enzyme previously associated with bipoloar disorder and schizophrenia, pleckstrin homology domain-containing family G member 3 (PLEKHG3), a guanide nucleotide exchange enriched in the brain, and churchill domain containing protein 1 (CHURC1), homologs of which regulate neuronal development in model organisms. While a similar deletion has previously been reported in a family with spherocytosis, severe learning disabilities, and mild mental retardation, this is the first implication of chr14q23.2-23.3 in the etiology of autism and points to MTHFD1, PLEKHG3, and CHURC1 as potential candidate genes contributing to autism risk.

How has Leucovorin Calcium been used within the mitochondrial community to treat disorders of folate associated with mitochondrial dysfunction?

Within the Mito community, Leucovorin Calcium (high dose folinic acid) has been used for many different abnormal lab studies associated with mitochondrial dysfunction.

  1. for dopaminergic neurotransmitter disorders (note that, in order to make a neurotransmitter abnormality diagnosis, the child needs to have a lumbar puncture and specific testing for CSF neurotransmitters.)
  2. low CSF BH4 (tetrahydrobiopterin)
  3. when cerebral folate deficiency is highly suspected or confirmed through a lumbar puncture
  4. treatment of Kearns-Sayre syndrome  (a known mitochondrial myopathy)
  5. and more recently Leucovorin Calcium has been considered standard treatment for those with mtDNA depletion.  (note that, MtDNA depletion can be diagnosed with blood or tissue studies - e.g. the Baylor tests).

Baylor College of Medicine: http://www.bcm.edu/geneticlabs/?PMID=9246

As stated above, the autism/biomed community has been using folinic acid in the treatment of children with autistic spectrum disorders for some time.  The form of folinic acid frequently used was an over the counter folinic acid supplement.  However, recently, the autism biomed community has begun using prescription Leucovorin Calcium and the results look promising for some children with ASD and positive cerebral folate receptor autoantibodies labs. 

What are folate receptor autoantibodies (FRA) and how are testing and treating FRA's potentially helpful in kids with autism?

Dr. Edward Quadros, a researcher studying folate receptor antibodies from the Department of Biochemistry at SUNY Downstate Medical Center, states that "folate receptor blocking antibody is defined as an antibody that blocks the binding of folic acid to the folate receptor."

Folate receptor autoantibodies (FRA) disrupt the transport of folate across the blood-brain barrier potentially resulting in low concentrations of folate.  In January of 2012, Dr. Richard Frye et al. published an article looking at the prevalence of cerebral folate receptor autoantibodies in children with autism spectrum disorder and children's responses to Leucovorin Calcium, when FRA's are present. 

Here is the abstract from Molecular Psychiatry, Cerebral Folate Receptor Antibodies in Autism Spectrum Disorder:

Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood- brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2mgkg_1 per day; maximum 50mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.

In this research, it was found that "an unexpectedly high prevalence (75.3 %) of FRA's was found in 93 children with ASD without significant neurological abnormalities."  And, "two-thirds of the treated children [with Leucovorin Calcium] were perceived as obtaining some benefit and about one-third had a moderate or much improvement in cognitive-behavioral dimensions", which included verbal communication, receptive and expressive language, attention and stereotypical behavior.  "This study demonstrates an unexpectedly high FRA prevalence and a favorable response to Leucovorin Calcium in FRA-positive children with ASD".  To read the full text, please visit this link:

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2011175a.html

What's the possible connection between FRA's and mitochondrial dysfunction?

Frye et al. stated, "Mitochondrial dysfunction, which has been associated with ASD, can contribute to reduced transport of folate across the blood-brain barrier."  And, "Deficits in folate one-carbon metabolism have been shown to promote methylation deficits and oxidative stress in some children with ASD." 

Given the benefits observed from Leucovorin Calcium (for several years now) within the mitochondrial community, it is intriguing to see such a large percent of positive responses to Leucovorin Calcium in autistic children with FRA.  Folate genes, inborn errors of folate metabolism and cerebral folate receptor autoantibodies may be contributing factors in the development of autistic symptoms in some children.  Research looking at the interaction of epigenetic factors on one-carbon (folate) metabolism pathway gene variants and its role in autism and mitochondrial dysfunction is needed.  There is much left to be learned about this possible connection.

Here are some relevant links to research on folate, mitochondrial disease and/or autism:

1. Cerebral folate deficiency syndromes in childhood: clinical, analytical, and etiologic
aspects (2011)

http://www.ncbi.nlm.nih.gov/pubmed/21555636

2. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate
deficiency syndrome
. (2008)

3. Mitochondrial complex I encephalomyopathy and cerebral 5-methyltetrahydrofolate deficiency. (2007)

4. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. (2007)
http://www.ncbi.nlm.nih.gov/pubmed/18461502

5. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. (2005)

6. Autoantibodies to Folate Receptors in the Cerebral Folate Deficiency Syndrome (2005)

 7. Cerebral folate deficiency: life-changing supplementation with folinic acid. (2005)

 8. Cerebral Folate Deficiency and Mitochondrial Disease.