Clinical characteristics: FOLR1-related cerebral folate transport deficiency (FOLR1-CFTD), resulting from loss of function of the folate receptor alpha (FOLR1) protein, causes cerebral folate deficiency in the absence of systemic folate deficiency. Individuals with untreated FOLR1-CFTD have very low cerebrospinal fluid (CSF) levels and progressive neurologic deterioration with developmental delays and progressive cognitive impairment, behavioral issues, seizures, and movement disorders that may progress to immobility. Despite these incapacitating neurologic findings, untreated individuals can live well into adulthood.

Treatment with 5-formyltetrahydrofolate (5-formylTHF; also known as folinic acid or leucovorin) can result in substantial improvement in neurologic findings when started at a young age. Treatment of asymptomatic or mildly symptomatic younger sibs at the time of diagnosis of their older sibs can either prevent the neurologic signs of this disorder or result in marked or complete regression of the neurologic findings.

Diagnosis/testing: The diagnosis of FOLR1-CFTD is established in a proband with biallelic FOLR1 pathogenic variants identified by molecular genetic testing.

Management: Targeted therapy: Treatment with 5-formylTHF can bring CSF folate levels into the normal range for the age of the individual. While oral administration is often sufficient, intramuscular administration may be necessary. Monitoring CSF folate levels is essential to ensure that the dose of 5-formylTHF is sufficient, particularly when the clinical response is inadequate or there is uncertainty about adherence.

Supportive care: Neurologic manifestations of untreated FOLR1-CFTD are treated per standard practice.

Surveillance: For those being treated with 5-formylTHF, the following is recommended for monitoring CSF folate levels, taking into consideration the complexity of lumbar puncture, particularly in infants and children: baseline CSF folate level obtained at the time of diagnosis; once treatment has begun, repeat CSF folate levels obtained to confirm that an adequate therapeutic dose and optimal clinical outcome has been achieved; repeat CSF folate levels if there are changes in the individual's clinical status (e.g., developmental delays or regression, new-onset neurologic findings, seizures) or if there are concerns regarding adherence; optimally and if feasible, yearly CSF folate levels until age five years.

Agents/circumstances to avoid: Folic acid is not used to treat FOLR1-CFTD because folic acid binds tightly to FOLR1, possibly interfering with FOLR1 function, which is a concern when treating individuals who have residual FOLR1 activity.

Evaluation of relatives at risk: Clarification of the genetic status of all sibs of a proband is recommended to identify as early as possible those sibs who would benefit from prompt initiation of treatment with 5-formylTHF. Newborns at risk should be evaluated for the familial FOLR1 pathogenic variants if molecular genetic testing was not performed prenatally.

Genetic counseling: FOLR1-CFTD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an FOLR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. If both pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing for FOLR1-CFTD are possible.