Dr C P Ravikumar

Folinic acid is a medication also commonly known as leucovorin. Although it is similar to folic acid (vitamin b9) in action, its chemical structure is different. Unlike folic acid, Folinic acid does not require to be activated by an enzyme (dihydrofolate reductase) in order to be used by the body and is therefore a biologically active folate.
Folate compounds (i.e. both Folic acid Folinic acid) are required for production of red blood cells in the bone marrow and are responsible for the maturation and maintenance of the nervous system. Therefore, folate deficiencies lead to abnormal and decreased formation of red blood cells, causing megaloblastic anemia, as well as defective formation of spinal cord or neural tube defects at birth, and neuro-psychiatric conditions in children and adults.
Treatment of these conditions require administration of folates either as vitamin supplements (folic acid) which provides the body with adequate systemic levels and is commonly used to manage anemias as well as a preventive measure during pregnancy to avoid neural tube birth defects. However, there are some neurological conditions where even though the level of folates is adequate in the body, it is unable to reach the brain or nervous tissue, due to a defect in the functioning of folate receptors. This is known as Cerebral Folate deficiency (CFD) syndrome, which causes neurodegeneration soon after birth.

Cerebral Folate Deficiency
This neurological syndrome is caused due to the inadequate supply of folate to the brain due to disrupted functioning of folate receptors (FRA or Folate Receptor Alpha). This may be caused because of auto- antibodies that bind to the FRA receptors, preventing the uptake of folates. A rare genetic condition, causing mutations in the FOLR1 gene, may also cause defective formation of the receptors, thereby decreasing folate uptake. This causes low levels of 5-methyly- tetrahydrofolate (5-MTHF)  in the cerebrospinal fluid surrounding the brain and spinal cord, which is necessary for the construction of protective layers (myelin) around nerves or chemical messengers (neurotransmitters) in the brain, which causes neurological complications.

Signs and Symptoms
  1. During early infancy: 4-6 months after birth
  • Irritability
  • Insomnia
  • Slow head growth leading to small head circumference
  • Low muscle tone (hypotonia)
  • Ataxia (loss of co-ordination)
  • Loss of voluntary movements (dyskinesia)
  • Constant contraction of muscles (spasticity)
  • Vision, speech or hearing defects
  1. At two years old
  • Psychomotor regression: children may lose the mental and motor skills they achieved so far
  • Intellectual disability
  • Developmental delay
  • Speech difficulty
  • Recurrent seizures

Diagnosis  
  1. Low levels of 5- MTHF in the cerebrospinal fluid (Obtained through lumbar puncture or spinal tap, where a needle is inserted into the spinal canal in the lower back, in order to draw out the CSF)
  2. MRI of the brain reveals irregular white matter (leukodystrophy) with atrophy of the frontal and temporal regions of the brain
  3. EEG (electroencephalography) shows irregular electrical activity of the brain
  4. Genetic testing may reveal mutations of the FOLR1 gene
  5. Tests for FRA autoantibodies may be positive
  6. Serum folic acid levels may be normal or reduced

Management  
Folinic acid is administered as  leucovorin calcium, and can be given orally, through an IV or injected into the muscle as an intramuscular medication. The dosage is dependent on factors like age, weight , height and type of health problems being treated and should therefore be determined by the treating physician. The earlier the treatment is started in CFD, the better the outcome achieved.

Other uses of Folinic acid
  1. Certain drugs like methotrexate which is used to treat rheumatoid arthritis cause side effects which are prevented or decreased by the use of  Folinic acid.
  2. It is used in combination with 5- fluorouracil, to treat colorectal cancer
  3. It may be used for the treatment of folate deficiency causing anemia

Side effects
It may cause nausea, vomiting or allergic reactions with facial flushing or itching. Medical attention is required if there is shortness of breath or closing up of the throat due to severe allergic reaction.   

Dr C P Ravikumar

Dr C P Ravikumar

CONSULTANT – PEDIATRIC NEUROLOGY
Aster CMI Hospital, Bangalore