Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution

Neuropediatrics. 2002 Dec;33(6):301-8. doi: 10.1055/s-2002-37082.


Introduction: Normal brain development and function depend on the active transport of folates across the blood-brain barrier. The folate receptor-1 (FR 1) protein is localized at the basolateral surface of the choroid plexus, which is characterized by a high binding affinity for circulating 5-methyltetrahydrofolate (5-MTHF).

Patients and methods: We report on the clinical and metabolic findings among five children with normal neurodevelopmental progress during the first four to six months followed by the acquisition of a neurological condition which includes marked irritability, decelerating head growth, psychomotor retardation, cerebellar ataxia, dyskinesias (choreoathetosis, ballism), pyramidal signs in the lower limbs and occasional seizures. After the age of six years the two oldest patients also manifested a central visual disorder. Known disorders have been ruled out by extensive investigations. Cerebrospinal fluid (CSF) analysis included determination of biogenic monoamines, pterins and 5-MTHF.

Results: Despite normal folate levels in serum and red blood cells with normal homocysteine, analysis of CSF revealed a decline towards very low values for 5-methyltetrahydrofolate (5-MTHF), which suggested disturbed transport of folates across the blood-brain barrier. Genetic analysis of the FR 1 gene revealed normal coding sequences. Oral treatment with doses of the stable compound folinic acid (0.5-1 mg/kg/day Leucovorin(R)) resulted in clinical amelioration and normalization of 5-MTHF values in CSF.

Conclusion: Our findings identified a new condition manifesting after the age of 6 months which was accompanied by low 5-MTHF in cerebrospinal fluid and responded to oral supplements with folinic acid. However, the cause of disturbed folate transfer across the blood-brain barrier remains unknown.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood-Brain Barrier / genetics
  • Blood-Brain Barrier / physiology
  • Brain Diseases, Metabolic, Inborn / cerebrospinal fluid
  • Brain Diseases, Metabolic, Inborn / drug therapy
  • Brain Diseases, Metabolic, Inborn / genetics*
  • Carrier Proteins / genetics
  • Child
  • Child, Preschool
  • DNA-Binding Proteins*
  • Erythrocytes / metabolism
  • Female
  • Folate Receptor 1
  • Folate Receptors, GPI-Anchored
  • Humans
  • Infant
  • Intellectual Disability / cerebrospinal fluid
  • Intellectual Disability / drug therapy
  • Intellectual Disability / genetics*
  • Leucovorin / administration & dosage
  • Leucovorin / blood
  • Male
  • Membrane Proteins / genetics
  • Membrane Transport Proteins*
  • Movement Disorders / cerebrospinal fluid
  • Movement Disorders / drug therapy
  • Movement Disorders / genetics*
  • Neurologic Examination
  • Paraplegia / cerebrospinal fluid
  • Paraplegia / drug therapy
  • Paraplegia / genetics*
  • Psychomotor Disorders / cerebrospinal fluid
  • Psychomotor Disorders / drug therapy
  • Psychomotor Disorders / genetics*
  • Receptors, Cell Surface*
  • Replication Protein C
  • Spinocerebellar Degenerations / cerebrospinal fluid
  • Spinocerebellar Degenerations / drug therapy
  • Spinocerebellar Degenerations / genetics*
  • Tetrahydrofolates / cerebrospinal fluid
  • Tetrahydrofolates / deficiency*
  • Transcription Factors*


  • Carrier Proteins
  • DNA-Binding Proteins
  • FOLR1 protein, human
  • Folate Receptor 1
  • Folate Receptors, GPI-Anchored
  • Membrane Proteins
  • Membrane Transport Proteins
  • RFC1 protein, human
  • Receptors, Cell Surface
  • SLC19A2 protein, human
  • Tetrahydrofolates
  • Transcription Factors
  • Replication Protein C
  • Leucovorin
  • 5-methyltetrahydrofolate