Clinical, etiological and therapeutic aspects of cerebral folate deficiency

Abstract

Cerebral folate deficiency is defined as any neurological condition associated with low cerebrospinal fluid folate concentrations. It is becoming increasingly associated with several neurological diseases, either genetic or environmental. Treatment of cerebral folate deficiency by folate supplementation is generally effective, improving the neurological outcome of some patients. However, to treat cerebral folate deficiency, the proper choice of one of the available folate forms is essential. The distinct brain folate metabolism features compared with peripheral folate metabolic pathways strongly suggest the investigation of different folate forms, such as the biologically active folinic acid and 5-methyltetrahydrofolate, since they are efficiently transported to the brain. Regarding the oral doses of the different folate forms, despite the fact that there are some recommendations, there is no general consensus. Further investigation and designing clinical trials are advisable to elucidate these aspects.

Keywords:

• 5-methyltetrahydrofolate
• cerebral folate deficiency
• choroid plexus
• folate transport and metabolism
• folic acid
• folinic acid
• neurological diseases

Acknowledgement

This article arises from the project InNerMeD-I-Network which has received funding from the European Union, in the framework of the Health Programme.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Folate is essential for brain metabolism and function.

• Cerebral folate deficiency is caused by either genetic or environmental factors.

• Regarding the genetic causes, the investigation of rare diseases of folate metabolism and transport has elucidated key mechanisms explaining cerebral folate deficiency.

• There is growing evidence of the implication of cerebral folate deficiency in the pathophysiology of other common diseases.

• The conventional treatment with folic acid (a non-biologically active form) is probably not suitable to correct cerebral folate deficiency, especially in diseases affecting folate transport and metabolism.

• For these genetic conditions, folinic acid and 5-methyltetrahydrofolate would be the first choice to correct cerebral folate deficiency.

• For nutritional or other environmental problems leading to cerebral folate deficiency, folic acid would be suitable as therapy, but only if dihydrofolate reductase and methylenetetrahydrofolate reductase activities are adequate.

• According to previous experiences, the study of cerebral folate status in different neurological diseases might detect cerebral folate deficiency in a noticeable number of cases, allowing the correction of this biochemical disturbance and improving the neurological outcome of patients.

Notes