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.
BACKGROUND
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).


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.


CONCLUSIONS
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.
Ramaekers
V T
VT
Division of Paediatric Neurology, Department of Paediatrics, University Hospital Aachen, Aachen, Germany. vramaekers@ukaachen.de
Häusler
M
M
Opladen
T
T
Heimann
G
G
Blau
N
N
D001812:Blood-Brain Barrier / Q000235:genetics / Q000502:physiology; D020739:Brain Diseases, Metabolic, Inborn / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D002955:Leucovorin / Q000008:administration & dosage / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D026901:Membrane Transport Proteins; D009069:Movement Disorders / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D009460:Neurologic Examination; D010264:Paraplegia / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D011596:Psychomotor Disorders / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D011956:Receptors, Cell Surface; D051818:Replication Protein C; D013132:Spinocerebellar Degenerations / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics*; D013763:Tetrahydrofolates / Q000134:cerebrospinal fluid / Q000172:deficiency*; D014157:Transcription Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C548696:FOLR1 protein, human; D058975:Folate Receptor 1; D058973:Folate Receptors, GPI-Anchored; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C081632:RFC1 protein, human; D011956:Receptors, Cell Surface; C120043:SLC19A2 protein, human; D013763:Tetrahydrofolates; D014157:Transcription Factors; D051818:Replication Protein C; D002955:Leucovorin; C005984:5-methyltetrahydrofolate