Cerebral Folate Deficiency via the FOLR1 Gene

Cerebral folate deficiency (CFD) is a neurometabolic disorder caused by reduced levels of folate in the brain. CFD patients typically present with global developmental delay around 2 years of age. Common symptoms seen in CFD patients include hypotonia, ataxia, myoclonic seizures, and athetoid movements (Grapp et al. 2012). Moderate to severe psychomotor regression is observed following disease onset. Patients are intellectually disabled, lack language, and have an increased incidence of aggressive behavior. If left untreated, patients develop frequent refractory seizures and are often wheelchair-bound due to worsening motor symptoms. MRI reveals abnormal myelination of the periventricular and subcortical white matter as well as cerebellar atrophy. Metabolite analysis reveals low 5-methyl-tetrahydrofolate levels in cerebrospinal fluid (CSF), but a normal folate metabolism profile in plasma. This CSF-plasma difference helps distinguish CFD from other folate deficiency syndromes (Pérez-Dueñas et al. 2010).

Oral folinic acid supplementation was found to greatly improve symptoms, particularly seizures and motor abnormalities, in affected individuals (Pérez-Dueñas et al. 2010; Grapp et al. 2012). Early folinic acid treatment at first clinical onset was reported to completely reverse CFD symptoms (Steinfeld et al. 2009).

Cerebral folate deficiency is inherited in an autosomal recessive manner and can be caused by variants in the FOLR1 gene. Nonsense, missense, and splice site variants as well as small duplications in FOLR1 have been reported to cause cerebral folate deficiency (Grapp et al. 2012). Other reported causes of CFD include: autoantibodies directed against the FOLR1 protein, mitochondrial disorders, and Rett syndrome (Ramaekers et al. 2013).

Folate derivatives are essential cofactors required for many biological processes, including DNA synthesis. Dietary folate is metabolized in the liver to the physiologically active form 5-methyl-tetrahydrofolate (5MTHF) which is then distributed by the bloodstream (Hyland et al. 2010). Humans possess multiple folate receptors, and folate receptor-alpha appears to be the primary receptor responsible for transporting 5MTHF across the blood-CSF barrier in adults (Steinfeld et al. 2009). FOLR1 encodes the cerebral folate receptor-alpha. Loss of FOLR1 results in greatly reduced levels of 5MTHF in the brain. Supplementation with folinic acid increases serum levels of 5MTHF and increases the amount of 5MTHF transported to the CSF via other low affinity folate transporters (Ramaekers et al. 2013).

FOLR1 was sequenced in 72 patients with low levels (<40nmol/l) of 5MTHF in cerebrospinal fluid. Pathogenic FOLR1 variants were identified in 10 (~14%) patients (Grapp et al. 2012). The authors noted that of the 14 patients that had extremely low CSF 5MTHF levels (<5nmol/l), 10 (~70%) had pathogenic FOLR1 variants.

This test provides full coverage of all coding exons of the FOLR1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.