Cerebral folate deficiency in adults: A heterogeneous potentially treatable condition

J Neurol Sci. 2019 Jan 15:396:112-118. doi: 10.1016/j.jns.2018.11.014. Epub 2018 Nov 10.


Objective: To describe the phenotype and the response to folinic acid supplementation of cerebral folate deficiency (CFD) in adults, a disorder diagnosed on low 5-methyltetrahydro-folate (5MTHF) in cerebrospinal fluid (CSF), which can correspond to a inherited disorder of folate metabolism (IDFM) or to a metabolic consequence of various neurological diseases.

Methods: We conducted a retrospective study on 224 adult patients with neurological symptoms who had a 5MTHF CSF dosage, collecting their neurologic and neuroimaging data.

Results: 69 patients had CFD (CSF 5MTHF level < 41 nmol/L), 25 of them had severe CFD (sCFD; ≤25 nmol/L) with adult onset neurological symptoms in 41%. 56% of sCFD patients had an underlying identified neurologic disorder, mainly mitochondrial diseases, hepatic encephalopathy and primary brain calcifications (no identified IDFM), the others were classified as undiagnosed. sCFD patients presented most frequently pyramidal syndrome (75%), movement disorders (56%), cerebellar syndrome (50%) and intellectual disability (46%). MRI findings mostly showed white matter abnormalities (WMA; 32%) and calcifications (12%), and were normal in 23%. The clinico-radiological phenotype of sCFD patients was not clearly different from non CFD patients in terms of manifestations frequency. However, their neurological picture was more complex with a higher number of combined neurological symptoms (4.7±1.6 vs 3.4±1.7, p = .01). In Magnetic Resonance Spectroscopy (MRS), Choline/Creatine (Cho/Cr) ratio was lower in sCFD patients (n = 7) compared to non-CFD patients (n = 73) (p = .005), with good sensitivity (71%) and excellent specificity (92%). Among twenty-one CFD patients treated with folinic acid, nine had a sustained improvement, all with sCFD but one (50% of sCFD patients improved). In two undiagnosed patients with extremely low 5MTHF CSF values, MRI WMA and low Cho/Cr ratios, folinic acid treatment leaded to a dramatic clinical and radiological improvement.

Conclusion: CSF 5MTHF dosage should be considered in patients with mitochondrial diseases, primary brain calcifications and unexplained complex neurological disorders especially if associated with WMA, since folinic acid supplementation in patients with sCFD is frequently efficient.

Keywords: Brain MRI; Cerebral folate deficiency; Inherited disorders of metabolism.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Calcinosis / diagnostic imaging
  • Calcinosis / etiology
  • Calcinosis / genetics
  • Cerebellar Diseases / cerebrospinal fluid
  • Cerebellar Diseases / complications*
  • Cerebellar Diseases / diagnostic imaging
  • Cerebellar Diseases / genetics
  • Child
  • Child, Preschool
  • Female
  • Folic Acid / cerebrospinal fluid
  • Folic Acid Deficiency / cerebrospinal fluid
  • Folic Acid Deficiency / complications*
  • Folic Acid Deficiency / diagnostic imaging
  • Folic Acid Deficiency / genetics*
  • Follow-Up Studies
  • Humans
  • Infant
  • Infant, Newborn
  • Intellectual Disability
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mitochondrial Diseases / diagnostic imaging
  • Mitochondrial Diseases / etiology
  • Mutation / genetics*
  • Proteins / genetics*
  • Retrospective Studies
  • Tetrahydrofolates / cerebrospinal fluid
  • White Matter / diagnostic imaging
  • White Matter / pathology
  • Young Adult


  • Proteins
  • SPG11 protein, human
  • Tetrahydrofolates
  • Folic Acid
  • 5-methyltetrahydrofolate