ABSTRACT
Cerebral folate transporter deficiency syndrome, caused by FOLR-1 mutations is characterized by late infantile onset, severe developmental regression, epilepsy, and leukodystrophy. An extremely low concentration of 5-methyltetrahydrofolate in the cerebrospinal fluid provides a crucial clue to its diagnosis and is a treatment target. Oral or intravenous folinic acid (5-formyltetrahydrofolate) administration improves clinical symptoms and brain magnetic resonance imaging (MRI) findings. We describe three siblings carrying a novel homozygous FOLR1 nonsense mutation, that were referred due to intractable epilepsy and progressive neurological decline. Brain MRI showed hypomyelination and cerebellar atrophy. Folinic acid (oral and intravenous) supplementation, initiated after over 15 years illness, has failed to result in any sizeable clinical or neurophysiological improvement. Cerebral folate transport deficiency bears overlapping clinical features with many severe developmental encephalopathies. It is crucial to recognize FOLR1 signs and establish an early clinical and molecular diagnosis in order to provide timely folinic acid treatment and improve outcome.
Subject(s)
Folate Receptor 1/deficiency , Genetic Association Studies , Genetic Predisposition to Disease , Neuroaxonal Dystrophies/diagnosis , Neuroaxonal Dystrophies/genetics , Siblings , Adolescent , Alleles , Brain/diagnostic imaging , Brain/drug effects , Brain/pathology , Consanguinity , Developmental Disabilities/diagnosis , Developmental Disabilities/genetics , Disease Management , Epilepsy/diagnosis , Epilepsy/genetics , Female , Folate Receptor 1/genetics , Folic Acid/administration & dosage , Genetic Testing , Genotype , Humans , Magnetic Resonance Imaging , Male , Mutation , Neuroaxonal Dystrophies/therapy , Phenotype , Syndrome , Treatment OutcomeABSTRACT
The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human α-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor.