Stepwise adaptation of treatment with calcium folinate in different modes of application leads to optimal therapeutic results for patients with cerebral folate transport deficiency

Aims: Cerebral folate transport deficiency (CFTD) is an autosomal recessively inherited disease that is caused by a brain-specific folate transport defect. All currently known patients show very low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid and develop an encephalopathy after the second year of life. We investigated patients suffering from CFTD to understand the phenotypic spectrum and to enable individual optimization of treatment.

Methods: Clinical data of a total of 12 patients with proven pathogenic mutation in the F0LR1 gene were compared respectively. Onset of disease, initial symptoms, frequency and type of cerebral seizures, motor deficits, signs of spasticity, behavioral abnormalities, head circumference, abnormalities in the cranial MRI as well as in the EEG and the medications were considered.

Results: All investigated patients showed ataxia, delayed myelination, and cerebellar atrophy in the cranial MRI as well as slow background EEG with multifocal epileptiform activity. Most patients demonstrated myoclonic epilepsy, autistic symptoms, dystonia and microcephaly. Focal lesions in the cerebral white matter and signs of global brain atrophy were found in the cranial MRI. Oral treatment with calcium folinate led to normalization of the measured 5MTHF concentration in the cerebral spinal fluid in all patients but was not associated with major improvements of clinical symptoms. In contrast, intravenous application of calcium folinate reduced or abolished the movement disorder and the cerebral seizures. In case of two patients, the disease state could significantly be improved by intrathecal therapy with calcium folinate.

Conclusion: Patients suffering from CFTD presents with a variable severity of clinical symptoms. The phenotypic variability cannot completely be explained by the mutation analysis in the F0LR1 gene but indicates additional contributing factors. A stepwise adaptation of the mode of calcium folate application according to the severity of symptoms results in individual optimization of therapeutic results.