Diagnostic Criteria

Suggestive Findings

FOLR1-related cerebral folate transport deficiency (FOLR1-CFTD) should be considered in a proband with the following clinical, laboratory, and brain MRI findings and family history. Clinical findings. Frank signs of FOLR1-CFTD usually occur after age one year but earlier presentations have been reported. The recognition of subtle signs as early as possible in an infant/ young child can facilitate early diagnosis and treatment, thereby substantially improving outcome.

• Subtle early signs evident during the first year of life

• Developmental delays, particularly in cognition, speech, and gait

• Signs that typically develop after age one year

Source: GeneReviews — "FOLR1-Related Cerebral Folate Transport Deficiency"

Differential Diagnosis

FOLR1-related cerebral folate transport deficiency (FOLR1-CFTD) is one of several causes of folate deficiency restricted to the central nervous system characterized by very low levels of cerebrospinal fluid (CSF) folate in the absence of clinically significant systemic folate deficiency. The differential diagnosis encompasses inherited disorders that impair either folate transport across the blood-choroid plexus-CSF barrier or folate metabolism in the brain, as well as cerebral folate deficiency associated with antibodies to the folate receptor alpha (FOLR1) protein. Recent reviews that include a comprehensive description of the differential diagnosis of cerebral folate deficiency are and . Impaired function of folate transporters.

Source: GeneReviews — "FOLR1-Related Cerebral Folate Transport Deficiency"

Management Guidelines

There are no established clinical practice guidelines for FOLR1-related cerebral folate transport deficiency (FOLR1-CFTD). Evaluations Following Initial Diagnosis To establish the extent of the disorder and needs in an individual diagnosed with previously untreated FOLR1-CFTD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. FOLR1-Related Cerebral Folate Transport Deficiency: Recommended Evaluations Following Initial Diagnosis

Source: GeneReviews — "FOLR1-Related Cerebral Folate Transport Deficiency"

Surveillance Guidelines

To monitor existing manifestations, the response to 5-formylTHF targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in this section are recommended. For affected individuals who are being treated with 5-formylTHF, in the absence of published guidelines, the following schedule for monitoring CSF folate levels is recommended:

• A baseline CSF folate level should be obtained at the time of diagnosis.

• Once treatment is begun, repeat CSF folate levels should be obtained (before the following dose) after two to three weeks to confirm that an adequate therapeutic dose has been achieved, thereby optimizing the clinical outcome.

• CSF folate levels should be repeated 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, a CSF folate level should be obtained yearly to age five years.

Table 7.

FOLR1-Related Cerebral Folate Transport Deficiency: Recommended Surveillance

System/Concern | Evaluation | Frequency

Neurologic

| • Monitor for new- onset or changes in seizure type frequency.

• Assess for other manifestations such as changes in gait, ataxia, tremor, other movement disorders.

| Per treating neurologist

Developmental delay/

Intellectual disability

| • Monitor developmental progress, cognition, educational needs.

Source: GeneReviews — "FOLR1-Related Cerebral Folate Transport Deficiency"