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Cerebral Folate Deficiency - what is it and who's at risk?

Cerebral folate deficiency (CFD) occurs when the amount of the active form of folate or 5-methyltetrahydrofolate (5-MTHF) in the brain is diminished in the presence of normal folate metabolism outside the central nervous system.

CFD can be due to the generation of antibodies against the folate receptor required to transport 5-MTHF into the CSF or mutations  in the folate receptor 1 gene (FOLR1). However, there are likely other causes given that CFD has been reported in a number of other disorders including both Down and Rett syndrome, Aicardi- Goutieres syndrome, a number of metabolic disorders (3 phosphoglycerate dehydrogenase deficiency, dihydropteridine reductase deficiency, aromatic amino acid decarboxylase deficiency) including mitochondrial disease, specifically Kearns-Sayre syndrome. Many patients with autism have also been shown to have CFD. In addition, deficiency of 5-MTHF has been linked to the chronic use of anti-folate or anticonvulsant drugs.

In classic CFD due to mutations in the FOLR 1 gene affected children have normal development during infancy but around two years of age (some articles report as young as four months) they begin to lose previously acquired mental in movement abilities demonstrating psychomotor regression. They develop speech problems and recurrent seizures, tremors, ataxia and often white matter disease.  Additional reported issues include sleep disturbance and increasing irritability.

The first case of Kearns-Sayre syndrome associated with decreased cerebral spinal fluid folate was reported by Dimauro et al in 1983. CFD and leukoencephalopathy was reported to be associated with a mitochondrial DNA deletion in the Annals of Neurology in 2006. The reported patient had an incomplete form of Kearns-Sayre syndrome. One year following supplementation with folinic acid, white matter changes had almost completely resolved in that patient. In 2007 a case of a mitochondria complex one encephalomyelopathy and cerebral folate deficiency was reported indicating that this issue may be present in mitochondrial patients other than those with Kearns-Sayre syndrome. Folate transport to the brain depends on ATP driven folate receptor mediated transport across choroid plexus epithelial cells. Folinic acid therapy along with other free radical treatment resulted in partial clinical improvement and the reversal of abnormal myelination patterns on neuro imaging in this patient.

In 2014, a group reported follow up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome and reported that four of the six patients showed disease progression over a study time of 1 to 8 years despite treatment while only one who was treated in the early stages of the disease exhibited both neurological  and radiological improvements whereas one of the two patients who showed long-term improvement showed neurological improvement only. Their findings suggest that early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of Kearns-Sayre syndrome specifically.

Our experience has been similar in regards to variable response to folinic acid supplementation in a variety of patients with mitochondria disease. For example, one child with Leigh disease who was found to have a diminished 5-MTHF CSF level at time of diagnosis during very early childhood showed continued disease progression including worsening seizures despite therapy. Other adults with specific findings have shown improvement with folinic acid therapy.

Although definitive diagnosis of cerebral folate deficiency requires a spinal tap and testing, many patients are apprehensive about undergoing such an invasive procedure for diagnosis since complications do occur such as spinal leaks that will at times require blood patches for resolution. Therefore, in some specific cases, we've instituted the use of leucovorin therapy without having them undergo the invasive spinal tap procedure particularly given the relative safety of this therapy.

In summary, CFD is a clear problem as an independent disease and in association with a number of other disorders to include mitochondrial disease.  However, many patients come to presentation and diagnose at variable times in their disease process making the institution of treatment at a set stage difficult or impossible.  In addition, many patients are apprehensive about undergoing invasive procedures & testing for clearly understandable reasons. As such, I believe that leucovorin therapy should be a consideration made by your expert and especially for those who are exhibiting through other testing or clinical presentations a high risk for this comorbid problem, regardless of proximity to diagnosis and despite lack of definitive confirmation through spinal fluid analysis given some possibility of improvement in clinical symptoms.


Fran Kendall, M.D.

This post is not meant to be a recommendation or a substitute for professional advice and services rendered by qualified doctors, allied medical personnel, and other professional services. The responsibility for any use of this information, or for proper medical treatment, rests with you.