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.
• Cerebral folate deficiency may be caused by decreased ability to transport folate across the blood-brain barrier because of decreased function of folate receptor alpha or due to specific disorders of folate metabolism.
• Cerebral folate deficiency due to folate transport disorders can be caused by blocking autoantibodies against folate receptor alpha or mutations in the FOLR1 gene.
• Affected individuals with cerebral folate deficiency due to mutations in the FOLR1 gene are normal at birth, but usually in the first year of life these children exhibit deceleration of head growth and developmental delay or regression, usually in the first year of life.
Historical note and terminology
Neurologic disease was first linked to folate deficiency in 1973 (38) and low CSF folate levels were first reported in 1981 (06). Cerebral folate deficiency was first reported by Ramaekers and colleagues in 2002 (32). As originally defined in 2004 by Ramaekers and Blau, cerebral folate deficiency is characterized by extremely low concentrations of 5-methyltetrahydrofolate (MTHF), the predominant circulating form of folate, in the cerebrospinal fluid in the presence of normal blood folate concentrations (30; 21).
The term “cerebral folate deficiency” is also sometimes used to describe conditions where CSF MTHF is low, in the presence of low or undefined peripheral folate levels (27), although this muddies the concepts and is confusing.
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 (30); however, because the etiology is known, the “idiopathic” descriptor seems inappropriate. More recent categorizations of disorders of folate metabolism have classified cerebral folate deficiency into primary and secondary forms (27).
Primary causes of cerebral folate deficiency include various inborn errors of metabolism:
• Folate receptor alpha (FRα) deficiency
• Dihydrofolate reductase (DHFR) deficiency
• Methylenetetrahydrofolate reductase (MTHFR) deficiency
• Methenyltetrahydrofolate synthetase (MTHFS) deficiency
Secondary causes of cerebral folate deficiency include a diverse collection of disorders, for many of which the precise metabolic disruption remains obscure:
• Antibodies to folate receptor alpha
• Mitochondrial disorders (especially Kearns-Sayre syndrome)
• Serine deficiency syndromes
• Dihydropteridine reductase (DHPR) deficiency
• Aromatic l-amino acid decarboxylase (AADC) deficiency
• Folinic acid-responsive seizures (allelic with pyridoxine-dependent epilepsy)
Secondary cerebral folate deficiency in adults, when defined simply as low MTHF concentrations in the CSF (in the presence of undefined peripheral folate levels), is a heterogeneous but potentially treatable condition (20). Cerebral folate deficiency in adults should be considered in patients with mitochondrial diseases, primary brain calcifications, and unexplained complex neurologic disorders, especially if associated with white matter abnormalities (20).
Disorders that produce low CSF 5-MTHF and low peripheral total folate include the following conditions:
• Nutritional deficiency of folate
• Antifolate drugs (eg, methotrexate, pemetrexed)
• Proton-coupled folate transporter (PCFT1) deficiency
This article will address the primary causes of cerebral folate deficiency and the disorder resulting from antibodies to the folate receptor. Collectively, these conditions include metabolic recycling defects and disorders of folate transport that typically present with extremely low cerebrospinal fluid concentrations of 5-MTHF below 10 nmol/L prior to treatment.