Folate-receptor alpha ( FOLR1 ) is of central importance for folate transport across the blood–brain barrier via the choroid plexus. Autoantibodies against folate receptors were identified as the cause of the infantile-onset cerebral folate deficiency (CFD) syndrome.1 In addition, FOLR1 is important for neural tube closure during embryogenesis.2,3 Here we report siblings with compound heterozygosity for 2 FOLR1 mutations causing congenital CFD. ### Clinical presentation. A 5-year-old boy developed normally until the age of 30 months. Thereafter, resting and intention tremor evolved, followed by ataxia, progressive speech disturbances and loss of motor capabilities, general hypotonia, apathy, and autism. Myoclonic-astatic seizures occurred at age 3.3 years. EEG showed slowing of the background activity, paroxysmal dysrhythmia with high-amplitude delta waves, and centrotemporal epileptic potentials bilaterally. Cranial MRI indicated delayed cortical myelinization. Blood count, serum, and erythrocyte folate were normal (table e-1 on the Neurology ® Web site at www.neurology.org). CSF analysis revealed 5-methyltetrahydrofolate (5MTHF) below the detection limit. The patient was treated with folinic acid starting with 0.5 mg/kg/day with subsequent dose escalation to 5 mg/kg/day. The treatment led to a normalization of CSF 5MTHF (54 nmol/L) associated with a remarkable clinical improvement including the ability to sit free, to walk with assistance, and to engage in social contacts. Seizure frequency decreased. ### FOLR1 DNA analysis. The clinical signs and symptoms were similar to those of patients with the infantile onset CFD syndrome.1 However, the age at clinical onset and the need for much higher therapeutic doses of folinic acid as compared to patients with infantile-onset CFD prompted us to search for a different underlying cause. Thus, we performed a sequencing …