How do you diagnose cerebral folate deficiency?

Diagnosing Cerebral Folate Deficiency

The definitive diagnosis of cerebral folate deficiency requires measurement of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF), which will show low levels despite normal peripheral folate status. 1, 2

Diagnostic Approach

Primary Diagnostic Test

• Measurement of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) is the gold standard for diagnosis 1, 2, 3
• Cerebral folate deficiency is defined as low CSF 5-MTHF levels in the presence of normal peripheral folate status 1, 4

Supporting Laboratory Tests

• Serum/plasma folate levels should be measured (normal is ≥10 nmol/L) 5
• Red blood cell folate should be measured (normal is ≥340 nmol/L) as it reflects long-term folate status 5
• Plasma homocysteine levels should be measured as a functional marker of folate status 5
• Vitamin B12 status must be assessed simultaneously, as deficiency can present with similar symptoms 5
• Methylmalonic acid levels should be checked to differentiate isolated folate deficiency from B12 deficiency 5

Analytical Methods

• Microbiological assay (MBA) using Lactobacillus rhamnosus is considered the gold standard for folate measurement 5
• Liquid chromatography-mass spectrometry (LC-MS) can be used to quantify different folate forms with good sensitivity and precision 5
• Protein binding assays are available but have limitations in affinity for different folate forms 5

Clinical Presentation Suggestive of Cerebral Folate Deficiency

Early Signs (typically beginning around 4 months of age)

• Irritability and sleep disturbances 1, 2
• Deceleration of head growth 1, 2

Progressive Neurological Symptoms

• Psychomotor retardation 1, 2
• Cerebellar ataxia 1, 3
• Spastic diplegia or paraplegia 1, 2
• Dyskinesia and movement disorders 2, 3
• Epilepsy (in approximately one-third of cases) 2, 4

Later Manifestations

• Visual disturbances (typically developing around age 3 years) 1, 2
• Progressive sensorineural hearing loss (typically starting from age 6 years) 1, 2

Differential Diagnosis and Associated Conditions

Primary Causes

• Folate receptor 1 (FOLR1) gene mutations 1, 4
• Autoantibodies against folate receptors 1, 2

Secondary Causes

• Metabolic disorders:

  • MTHFR deficiency 3, 4
  • Dihydrofolate reductase deficiency 4, 6
  • Serine deficiency 4, 6
  • Mitochondrial disorders (e.g., Kearns-Sayre syndrome) 2, 3

• Neurological syndromes:

  • Rett syndrome 5, 2
  • Aicardi-Goutières syndrome 1, 2

• Other factors:

  • Antifolate medications 2, 4
  • Anticonvulsant drugs 2, 4
  • Immune response activation 4, 6

Neuroimaging Findings

• Atrophy of frontotemporal regions 2, 3
• Periventricular demyelination 2, 3
• Progressive supra- and infratentorial atrophy 2, 3
• Some patients may have normal neuroimaging findings 2, 3

Treatment Considerations

• Oral folinic acid (5-formyltetrahydrofolate) is the treatment of choice 2, 6
• Starting dose typically 0.5-1 mg/kg/day, with some patients requiring 2-3 mg/kg/day 2, 6
• Folic acid supplementation is contraindicated as it may exacerbate CSF 5MTHF deficiency 1, 6
• Follow-up CSF analysis should be performed after 4-6 months of treatment to adjust dosing 2, 6

Important Clinical Pitfalls

• Do not confuse with systemic folate deficiency, which affects both peripheral and central nervous system folate levels 1, 4
• Always measure vitamin B12 simultaneously, as supplementation with folate alone can mask B12 deficiency while allowing neurological damage to progress 5
• Earlier diagnosis and treatment (before age 6) is associated with better outcomes 2, 6
• Regular clinical and EEG monitoring should be performed at 1,3, and 6 months after starting treatment 2, 6