Cerebral Folate Deficiency

What Causes Cerebral Folate Deficiency?

CFD is caused by a complex chain reaction that ultimately results in a folate deficiency in the brain. The first link in the chain is the dysfunction of a protein called folate receptor alpha (FRA). FRA’s job is to bind with folate and allow cell entry. In a part of the brain called the choroid plexus, folate is transported into the cerebrospinal fluid (CSF), which nourishes and protects the brain and spinal column. When FRA does not work correctly, folate levels in the CSF drop, resulting in damage to the brain that produces the disorder’s symptoms.

FRA dysfunction can be caused by several factors, including:

• Autoimmune reactions. In this case, the body’s immune system mistakenly attacks FRA and impairs its function.
• Metabolic disorders. These disorders disrupt energy production inside cells, depriving FRA of the fuel it needs to function.

Gene mutations. Abnormal changes in the FOLR1 gene interfere with the production of FRA. In these cases, FRA is either dysfunctional or produced in insufficient quantities.

Is Cerebral Folate Deficiency Hereditary?

Autoimmune reactions are the most common cause of CFD, and in these cases, the disorder is not inherited. However, CFD caused by mutations in the FOLR1 gene is inherited in an autosomal recessive pattern: a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop the disease but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with the disorder with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

How Is Cerebral Folate Deficiency Detected?

The most apparent symptoms of CFD, including psychomotor regression, are often not evident until early childhood, but signs of the disorder may begin to appear in infancy. Early detection of CFD is vital because treatment seems to be the most effective when started as soon as possible.

Early signs of CFD may include:

• Irritability
• Sleep problems (insomnia)
• Slow head growth
• Weak muscle tone

How Is Cerebral Folate Deficiency Diagnosed?

A doctor may suspect CFD if a child exhibits symptoms of the disorder such as coordination problems, small head size, or weak muscle tone. If this is the case, the doctor will conduct exams and tests to rule out other possible causes for the symptoms and confirm the CFD diagnosis. The diagnostic process may include:

• Physical exams and neurological exams to rule out other possible causes of the symptoms
• Hearing and vision exams
• Lumbar puncture (spinal tap) to look for low levels of folate in the CSF
• Electroencephalography (EEG) to measure the brain’s electrical activity. CFD may produce distinctive, unusual brain wave patterns.
• Blood tests to look for antibodies associated with autoimmune CFD
• Genetic testing to look for FOLR1 mutations associated with CFD

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Cerebral Folate Deficiency Treated?

Treatment of CFD may be effective, especially if started early. The oral supplement leucovorin calcium (also known as folinic acid) has been shown to improve folate levels in the CSF and subsequently improve the disorder’s neurological symptoms. Because some scientists believe that autoimmune CFD may be triggered by milk exposure, adopting a milk-free diet may be recommended in conjunction with leucovorin calcium.

Supplementation with folic acid, a B vitamin recommended for women during pregnancy, is not recommended for children with CFD. Folic acid may actually make CSF folate deficiency worse and exacerbate symptoms such as seizures.

How Does Cerebral Folate Deficiency Progress?

Left untreated, CFD can lead to severe complications that significantly reduce a child’s quality of life. Long-term complications can include:

• Worsening problems with coordination and muscle tone that lead to an inability to walk
• Intellectual impairment and autism-like symptoms
• Visual impairment
• Hearing loss 

How Is Cerebral Folate Deficiency Prevented?

Because the causes of CFD are not well understood and the deficiency often goes unnoticed until symptoms develop, there is no sure way to prevent the disorder. However, early detection and prompt treatment may slow the disease and prevent the worst complications.

Cerebral Folate Deficiency Caregiver Tips

Many people with CFD also suffer from other brain-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with CFD:

• CFD is sometimes associated with neurological disorders such as Aicardi-Goutierres syndrome and Kearns-Sayre syndrome.
• Autism has been associated with folate deficiency in some cases.
• Some studies have linked CFD to treatment-resistant depression.

Cerebral Folate Deficiency Brain Science

Although folate is present in cells throughout the body, it is especially prevalent in a part of the brain called the choroid plexus. The choroid plexus consists of blood vessels and specialized cells that produce cerebrospinal fluid (CSF). After it’s made in the choroid plexus, CSF travels through the central nervous system, where it surrounds, nourishes, and protects the brain and the spinal cord.

When the FRA protein functions properly in the choroid plexus cells, folate moves from the cells into the CSF and, subsequently, the rest of the brain. In brain cells, folate is essential for producing myelin, a fatty substance that surrounds some nerve cells, protecting them from damage and helping them communicate with one another. Folate also plays a role in producing neurotransmitters, chemicals crucial in communication between brain cells.

When the FRA protein is dysfunctional, folate levels in the CSF are low, leading to the breakdown of myelin in the brain. Without their protective myelin sheath, these cells don’t function correctly and eventually die. This condition is called leukodystrophy, and it causes the symptoms of CFD.

Cerebral Folate Deficiency Research

Title: The Myelin Disorders Biorepository Project (MDBP)

Stage: Recruiting

Principal investigator: Keith Van Haren, MD

Stanford University 

Palo Alto, CA

The Myelin Disorders Biorepository Project (MDBP) seeks to collect and analyze clinical data and biological samples from leukodystrophy patients worldwide to support ongoing and future research projects. The MDBP is one of the world’s largest leukodystrophy biorepositories, having enrolled nearly 2,000 affected individuals since it was launched over a decade ago.

Researchers working in the biorepository hope to use these materials to uncover new genetic etiologies for various leukodystrophies, develop biomarkers for use in future clinical trials, and better understand the natural history of these disorders. In addition, the knowledge gained from these efforts may help improve the diagnostic tools and treatment options available to patients in the future.

Genetic white matter disorders (leukodystrophies) are estimated to have an incidence of approximately 1:7000 live births. In the past, patients with white matter disease of unknown cause evaluated by the investigator achieved a diagnosis in fewer than 46% of cases after extensive conventional clinical testing. Even when a diagnosis is achieved, the diagnosis takes an average of eight years, and this “odyssey” results in testing charges to patients and insurers over $8,000 on average per patient, including patients who never achieve a diagnosis at all. With next-generation approaches such as whole-exome sequencing, the diagnostic efficacy is closer to 70%, but approximately a third of individuals do not achieve a specific etiologic diagnosis. These diagnostic challenges represent an urgent and unresolved gap in knowledge and disease characterization, as obtaining a definitive diagnosis is of paramount importance for leukodystrophy patients.

Moreover, the mechanisms of disease in many leukodystrophies of known cause are very poorly understood, with little known about the best symptomatic management and, thus, limited standards of care are available for the management of these patients.

The purpose of this study is to: (Aim 1) Define novel homogeneous groups of patients with unclassified leukodystrophy and work toward finding the cause of these disorders; (Aim 2) assess the validity and utility of next-generation sequencing in the diagnosis of leukodystrophies; (Aim 3) establish disease mechanisms in selected known leukodystrophies; (Aim 4) track current care and natural history of these patients to define the longitudinal course and determinants of outcomes in these disorders; (Aim 5) contact subjects for future research studies and/or clinical programs.

This biorepository will use available basic science and clinical research approaches to establish novel diagnoses, biomarkers, and outcome measures for future clinical diagnostic and therapeutic approaches.

Title: A Study of Serum Folate Levels in Patients Treated With Olaparib

Stage: Recruiting

Contact: Lois Winkelman, RN

Rush University Medical Center

Chicago, IL

This study investigates folate deficiency (lack of folic acid in the blood) in patients who take the drug olaparib to treat their advanced ovarian or breast cancer. The primary goal of this study is to determine the frequency and timing of folate deficiency and to learn more about whether giving folic acid supplements (vitamins) will help delay or avoid deficiency in these patients. Deficiency can cause doctors to reduce or stop treatment with olaparib. In this case, patients are not getting the best treatment for their cancer due to the unwanted side effect.

Title: Relative Bioavailability of Iron and Folic Acid in New Test Supplement

Stage: Completed

The Hospital For Sick Children

Toronto, ON

Deficiencies of iron and folic acid during pregnancy can lead to adverse outcomes for the fetus, thus supplements are recommended. Adherence to current tablet-based supplements is documented to be poor. Recently a powdered form of micronutrients has been developed, which may decrease side-effects and thus improve adherence. However, before testing the supplement’s efficacy as an alternate choice for supplementation during pregnancy, the bioavailability of the iron needs to be determined. This study aims to measure the relative bioavailability of iron and folic acid from a powdered supplement that can be sprinkled on semi-solid foods or beverages versus a traditional tablet supplement in pregnant women.