Cerebral folate deficiency

• Published in: Journal of inherited metabolic disease Vol. 33; no. 5; pp. 563 - 570
• Main Authors: Hyland, Keith, Shoffner, John, Heales, Simon J
• Format: Journal Article
• Language: English
• Published: Dordrecht Dordrecht : Springer Netherlands 01-10-2010; Springer Netherlands; Springer; Blackwell Publishing Ltd
• Subjects: Administration, Oral; Autoantibodies - cerebrospinal fluid; Biochemistry; Biological and medical sciences; Brain Diseases - cerebrospinal fluid; Brain Diseases - diagnosis; Brain Diseases - drug therapy; Brain Diseases - etiology; Dietary Supplements; Folate Receptor 1 - genetics; Folic Acid Deficiency - cerebrospinal fluid; Folic Acid Deficiency - diagnosis; Folic Acid Deficiency - drug therapy; Folic Acid Deficiency - etiology; Folic Acid Transporters - immunology; Genetic Predisposition to Disease; Human Genetics; Humans; Internal Medicine; Leucovorin - administration & dosage; Medical genetics; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mutation; Pediatrics; Review; Risk Factors; Tetrahydrofolates - cerebrospinal fluid; Tetrahydrofolates - deficiency; Treatment Outcome; Folinic Acid; Spinal Muscular Atrophy; Folate Deficiency; Rett Syndrome; Folate; Nutrition; Deficiency; Central nervous system; Vitamin; Genetics; Metabolic diseases; Folic acid; Encephalon; Genetic disease
• ISSN: 0141-8955; 1573-2665
• DOI: 10.1007/s10545-010-9159-6

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the concentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis.