Introduction

Cerebral folate deficiency (CFD) is a neurological developmental disorder caused by a lack of Vitamin B9 (folate) in the brain. It causes a wide range of symptoms, including impaired cognitive and motor abilities and behavioural problems. CFD is specifically a lack of Vitamin B9 in the cerebral spinal fluid (CSF), the fluid surrounding the brain, despite normal levels found in the blood. This difference is due to the receptors which transport folate into the brain being faulty or blocked. 

This article will cover prenatal origins of cerebral folate deficiency syndrome, the most common cause of CFD and how it begins with the immune system of pregnant mothers. Pregnant mothers' immune systems can produce autoantibodies which disrupt vitamin B9 from entering the baby's brain by blocking folate receptors. Vitamin B9, also known as folate, plays an essential role in a baby's brain metabolism and the brain's long-term development and function.¹

This article aims to clearly explain this condition, give an overview of the knowledge we currently have on the prenatal origin of CFD and highlight the importance of increased awareness and how it leads to early intervention and better outcomes for babies born with CFD.

Cerebral folate deficiency

Role of folate in brain development

Folate is essential for normal brain development. Folic acid, a synthetic form of Vitamin B9, is a recommended supplement for pregnant women to take, to support the baby’s normal development and prevent defects of the brain, skull and spinal cord, like spina bifida.² 

There is not much research on the underlying mechanisms of how folate supports neural development, but we do know some key aspects of neural development for which folate is essential.

Folate affects methylation, a process important for gene expression, so whether a gene is turned on or off is known as epigenetics. Gene expression affects various aspects of brain development. This is how folate supports cell growth, by allowing cells to make DNA to divide and multiply, processes which are essential for rapid tissue growth and development. This allows the developing neural tissue of the fetus to gain critical mass, which is important as the brain grows really fast during development.³

These mechanisms also explain why folate is essential for neural tube formation. This happens in the first 4 weeks of pregnancy. Folate, interacting with its receptor, triggers signals that help neural tube formation through the folding of the neural plate to form a tube structure. This is an essential part of embryonic development, and this structure later goes on to develop into the brain and spinal cord.³

Folate is also involved in the production of essential neurotransmitters, like dopamine and serotonin. These neurotransmitters are essential for normal cognitive function and mood regulation.⁴

From this, we understand how Vitamin B9 is essential from the very start of brain development, which is why autoantibodies from the mother that prevent the uptake of vitamin B9 in the fetus are a serious concern, as they prevent normal development.

Causes

Maternal autoantibodies and cerebral folate deficiency

Maternal autoantibodies are the cause of CFD in the majority of cases; they block the receptors through which folate is normally taken up into the brain.

Antibodies are proteins produced by your immune system. They are supposed to recognise foreign objects in your body, such as bacteria and viruses, and identify them to be destroyed, essentially protecting you from harmful substances that enter your body. Occasionally, your immune system can make a mistake; we refer to this as autoimmunity. Autoimmunity is when an antibody is produced by the immune system which recognises and targets a self-protein, a protein that should be there for the normal functioning of your body. When antibodies go wrong and start attacking your body, they can cause many problems, most notably that you would have heard of are autoimmune diseases such as lupus, type 1 diabetes, coeliac disease and rheumatoid arthritis^.5 

CFD, interestingly, is not a typical autoimmune disease; it can be referred to as a rare metabolic autoimmune syndrome, but only when it is specifically linked to autoantibodies which disrupt the uptake of folate into the brain, then can it be referred to as an autoimmune syndrome.⁶ 

Antibodies are passed from mother to fetus through the placenta. This is normally incredibly useful for the baby, as the mother can pass on her own immunity to help protect the baby from infection, since the baby’s immune system is not yet developed. In the case of CFD, which has prenatal origins, the mother can pass autoantibodies to the baby. In this case, these autoantibodies bind to folate receptors in the brain and block them from taking up folate into the brain.⁵ 

Other less common causes of cerebral folate deficiency include:⁷

• FOLR1 gene mutations — resulting in faulty folate receptor alpha proteins 
• Mitochondrial dysfunction — affecting folate transport into the brain

Symptoms 

Children with CFD can present a number of different cognitive and motor dysfunction symptoms, and can be observed in children as young as 4 months old. At this young age, the symptoms first observed are usually:¹

• Irritability
• Decelerated head growth
• Sleep problems

Other symptoms that emerge as the child becomes older:⁸

• Loss of previously acquired mental and motor abilities, speech difficulties
• Ataxia, difficulty with walking and balance
• Dyskinesias and spasticity, involuntary contraction and movement of muscles
• Spastic paraplegia (weakness and stiffness in the legs) 
• Epilepsy 
• Delayed development of motor skills 
• Loss of speech 

If left untreated, reports of visual disturbances from the ages of 3 and hearing loss in children from the ages of 6 have been documented. In some cases, autistic features may also be observed.⁸

Diagnosis

Over time, brain imaging, such as an MRI, can show some changes in the brain:⁹

• Loss of white matter in the brain: white matter is important for motor and cognitive functions
• Frontotemporal atrophy: this means shrinkage of the lobes at the front and sides of the brain, which control speech, behaviour, emotions, decision making and social behaviour
• Damage to the protective layer of nerves: damaging this insulating layer disrupts the smooth transmission of nerve signals. Damage to these subcortical structures in the brain can lead to impairments in motor control, emotional processing, learning, memory and cognitive functions

It is a complex condition to diagnose early on because routine tests will show normal levels of folate in the blood, but the problem here is the transport of this folate into the cerebrospinal fluid (CSF). When folate levels of the CSF are low, we can diagnose CFD. The levels of folate in the CSF can be tested through a procedure called a lumbar puncture, sometimes called a spinal tap. This is when a needle is inserted between the bones in your spine to extract some CSF, which can then be tested.⁸

Treatment

Folinic acid treatment 

High doses of Vitamin B9 are given immediately after diagnosis of CFD; this is either given as dl-folinic acid or levo-folinic acid. This is given based on body weight, and doses are started low and gradually increased; initially, they are given at half the final dose. This is because if folate concentrations in the brain are increased too abruptly, it causes a rapid increase in dopamine and serotonin levels, which is essentially an overstimulation of the brain, which can lead to irritation and aggression. It usually takes 6 weeks for the brain to adjust to the increase in Vitamin B9. Risperidone, an antipsychotic medication, can be given to relieve these symptoms.¹⁰ 

It has been shown that early treatments with high Vitamin B9 result in better outcomes and prognosis, and that if diagnosed and treated before 2 years of age, a child with CFD can see a full recovery. This is why raising awareness to support early diagnosis is essential.¹⁰ 

How a milk-free diet can improve outcomes in people with CFD

Research has shown that eliminating milk from the diet also has clinically significant outcomes for people with CFD. Proteins, specifically folate receptors, in animals’ milk can react with the autoantibodies present in people with CFD. This reaction can further trigger an immune response, increasing inflammation and further reducing the uptake of folate into the brain.¹¹ 

Why folinic acid is an effective treatment

Folinic acid enters the brain via a different route than folate. So, in someone with CFD whose folate receptors are blocked, we can use folic acid as treatment. Folinic acid enters the brain via a different receptor; this receptor is not as efficient as folate receptor alpha at transporting folate into the brain. This is why treatment is required in high doses, so it can have the same effect.¹²

Dl-folinic acid and levo-folinic acid (leucovorin calcium) are chemically slightly different to the folate we produce naturally; however, they can both be used therapeutically as a replacement because they carry out the same functions, especially in the brain. 

FAQ

Do high doses of folic acid supplementation promote seizures? 

Folic acid is considered generally safe, even when given in high doses, and is important for brain functioning. Some online sources highlight that folic acid may react with some anti-epileptic medications, but there is no recent literature to support these claims. It is important to speak to a healthcare professional before supplementing folic acid, especially if you are taking other medications.¹³ 

Summary

Cerebral folate deficiency is a rare condition, but its impact on individuals and families can be enormous. Increased awareness and understanding of CFD are crucial for earlier and more accurate diagnoses and for providing the quickest and most appropriate care. If you suspect CFD in your child or someone you know, watch for any early signs such as behavioural changes, delays in development or unusual movements. Early diagnosis and treatment can have a big impact, especially for infants, so it is important to raise any concerns you have with your health care professional.