Cerebral folate deficiency

Douglas J Lanska MD FAAN MS MSPH (Dr. Lanska of the Great Lakes VA Healthcare System and the University of Wisconsin School of Medicine and Public Health has no relevant financial relationships to disclose.)
Originally released October 16, 2012; last updated January 29, 2017; expires January 29, 2020

This article includes discussion of cerebral folate deficiency and idiopathic cerebral folate deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Cerebral folate deficiency is characterized by decreased cerebral concentrations of 5-methyltetrahydrofolate in the presence of normal blood folate concentrations within the reference range. Patients may have developmental delay or regression, hypotonia, seizures, visual disturbances, and autistic features. Therapy with oral folinic acid is effective for treating many aspects of the disorder. The disorder is caused by decreased transport of folate across the blood-brain barrier due to decreased function of folate receptor alpha. In some individuals, the disorder may be caused by autoantibodies directed against folate receptor alpha; in others, mutations in the FOLR1 gene, which encodes folate receptor alpha, have been identified.

Key points

 

• Cerebral folate deficiency is characterized by decreased ability to transport folate across the blood-brain barrier because of decreased function of folate receptor alpha.

 

• Affected individuals are normal at birth, but usually in the first year of life these children exhibit deceleration of head growth and developmental delay or regression.

 

• Affected individuals can develop hypotonia, dyskinesia, spasticity, and ataxia.

 

• They may develop seizures, visual and hearing loss, and autistic features.

 

• The disorder can be caused by blocking autoantibodies against folate receptor alpha or mutations in the FOLR1 gene.

 

• Treatment with folinic acid is partially effective.

Historical note and terminology

Cerebral folate deficiency was first reported by Ramaekers and colleagues in 2002 (Ramaekers et al 2002). The term “idiopathic cerebral folate deficiency” had been suggested to differentiate it from cerebral folate deficiency that can develop in disorders such as Rett syndrome or Kearns-Sayre syndrome (Ramaekers and Blau 2004); however, because the etiology is known, the “idiopathic” descriptor seems inappropriate.

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