image by: HWN

HWN Suggests

When Folate Can’t Get In: The Hidden Block That’s Sabotaging Your Child’s Brain

If you’ve been told your child might have low folate in the brain, you may have come across terms like folinic acid, leucovorin, MTHFR, or folate receptor antibodies. For many families, the next step seems obvious: add folate. But in practice, the story is far more complex... we’ve seen time and again that simply adding folinic acid does not always lead to major improvements. Sometimes it helps. Often, it doesn’t. And for some children, it can even make things worse.

read full article

Featured

 Cerebral Folate Deficiency and Folate Receptor Autoantibodies: A Treatable Detail in a Bigger Root Cause Picture

Cerebral Folate Deficiency (CFD) is a neurological condition characterized by low levels of 5-methyltetrahydrofolate (5-MTHF) in the cerebrospinal fluid (CSF), despite normal or elevated levels in the blood. This discrepancy arises when folate cannot effectively cross the blood-brain barrier, leading to insufficient folate in the brain. Folate is crucial for DNA synthesis, neurotransmitter production, and myelination, all vital processes for brain development and function. CFD can manifest with a range of neurological and developmental symptoms,

 Cerebral Folate Deficiency – a Unique Condition

Cerebral Folate Deficiency (CFD) is a neurological syndrome characterized by a severely decreased concentration of the active folate metabolite, 5-Methyltetrahydrofolate (5-MTHF), in the cerebrospinal fluid (CSF), despite typically normal folate levels in the blood. This condition highlights the critical distinction between systemic folate availability and central nervous system (CNS) folate utilization. CFD is not a single disease but a clinical entity with multiple potential causes, leading to a diverse range of neurological symptoms, often with onset in infancy and early childhood.

 Cerebral Folate Transport Deficiency

Cerebral folate deficiency can be caused by a fault in one of your inherited genes called the FOLR1 gene which codes for a receptor protein for folate. This protein (folate receptor alpha) is responsible for allowing Folate (Vitamin B9) entry into your body’s cells from the bloodstream. The Folate receptor alpha is mostly found within your brain and its role is for cognitive development and cognitive function. Another way that cerebral folate deficiency is caused is by your body’s own antibodies blocking the receptor for folate to bind to. This would not allow folate to cross the cell membrane within your brain. In the brain folate is necessary for making the fatty protective layer that surrounds nerves.

 In rare cases, scientists link autism to folate deficiency

“I suspect that children with the folate problem is a special subgroup of children with autism, but we donʼt know how big this subgroup is in the whole population,” says Ramaekers, head of the Center for Autism at the University of Liege in Belgium. Experts say children with autism should routinely be screened for folate deficiency. “Most doctors, especially if theyʼre psychiatry people, donʼt think about spinal taps in these cases,” says Chez. “But in a young child with severe motor delay, itʼs imperative to check that.” Though children with CFD have low levels of folate in their spinal fluid, folate levels in their blood are normal. “So the major hypothesis is that there has to be an abnormality in the transport of folate from the blood to the central nervous system,” Moretti explains. “The question for us is, what is the nature of that insult?”

Articles of Interest

Cerebral folate deficiency

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia.

Cerebral Folate Deficiency & Autism: Exploring a Hidden Connection and New Therapeutic Avenues

Several studies and clinical observations suggest that a subset of children with ASD also present with CFD. In many cases, they show elevated folate receptor autoantibodies, which impair folate delivery to the brain.

Cerebral Folate Deficiency in Autism

Autoimmune problems can cause the body to produce Folate Receptor Autoantibodies (FRAAs). These FRAAs block the transport of folate into the cerebral spinal fluid. FRAAs are being found at an alarming rate in children with autism. 71% of people with autism have autoantibodies that block folate from getting in the cell.

Cerebral Folate Deficiency in Autism - V. Ramaekers MD, University of Liege & Aachen

➤ Cerebral Folate Deficiency syndromes and their major origin attributed to folate receptor-alpha autoantibodies. ➤The discovery of severe infantile Autism associated with neurological deficits in a number of patients with Cerebral Folate Deficiency. ➤ Subsequent studies on brain folate deficiency in Autism Spectrum Disorders.

Cerebral Folate Deficiency in Children

Because FRA autoantibodies appear to be highly prevalent in children with ASD, we recommend that FRA autoantibody testing should be considered in all patients with ASD. Early identification and treatment is paramount, as younger children generally respond more robustly than older children, with “cure” reported in some children.

Cerebral Folate Deficiency Syndrome: Early Diagnosis, Intervention and Treatment Strategies

Cerebral folate deficiency syndrome (CFDS) is defined as any neuropsychiatric or developmental disorder characterized by decreased CSF folate levels in the presence of normal folate status outside the nervous system. The specific clinical profile appears to be largely determined by the presence or absence of intrauterine folate deficiency as well as postnatal age at which cerebral folate deficiency occurs. The primary cause of CFDS is identified as the presence of serum folate receptor-alpha (FRα) autoantibodies impairing folate transport across the choroid plexus to the brain...

Cerebral folate deficiency—mishaps and misdirection

Folic acid derivatives are important biological compounds that occupy key roles in a variety of cellular metabolic pathways including the synthesis of purines and thymidine, the remethylation of homocysteine to form methionine and the synthesis and breakdown of a number of amino acids, neurotransmitters and myelin (Watkins and Rosenblatt, 2012). Folates are critical for foetal development, and folate deficiency has been associated with an increased risk of congenital and post-natal problems including neural tube, cardiovascular and limb defects; cleft lip and palate; chromosomal disorders, such as Trisomy 21 and Fragile X and some paediatric malignancies including leukaemia and neuroblastoma.

Pharmacoresistant Epilepsy in Childhood: Think of the Cerebral Folate Deficiency, a Treatable Disease

Folates or vitamin B9 are essential to many biological processes such as DNA synthesis and repair, regulation of gene expression, amino acids (AA) metabolism, myelin formation and neurotransmitters synthesis. They are also well known to be involved in the neural tube formation during embryogenesis.

Resources

FRAT

FRAT®(Folate Receptor Autoantibody Test) is a diagnostic blood test that screens for autoantibodies to the Folate Receptor Alpha (FRa), known as Folate Receptor Autoantibodies. The presence of Folate Receptor Autoantibodies suggests that folate (vitamin B9), which is an essential vitamin for proper growth and neurological function, is not being properly transported to the brain and into cerebrospinal fluid (CSF), among other tissues where Folate Receptor Alpha may be found.

NORD

Cerebral folate deficiency is a neurological syndrome in which development is usually normal in the first year of life, but at approximately 2 years of age, affected children start to lose mental and motor skills (psychomotor regression). Some early symptoms are intellectual disability, speech difficulties, and development of recurrent seizures in a third of affected children. Motor issues such as tremors and lack of muscle control or coordination of voluntary movements (ataxia) can become severe.