Neurodegeneration Due To Cerebral Folate Transport Deficiency

A number sign (#) is used with this entry because of evidence that neurodegeneration due to cerebral folate transport deficiency is caused by mutation in the FOLR1 gene (136430) on chromosome 11q13.

Description

This is an autosomal recessive disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function (Steinfeld et al., 2009).

Clinical Features

Steinfeld et al. (2009) reported 2 German sibs with severe neurodegeneration beginning after age 2 years. The older boy, at age 3 years and 19 months, was severely handicapped, wheelchair-bound, and suffered from resistant epileptic seizures. After treatment with oral folinic acid, the frequency and severity of epileptic seizures declined, and the boy started to walk with support. His younger sister, by 2 years, was treated with folinic acid directly after the onset of her first motor symptoms at the age of 2 years and 3 months. She completely recovered and has not developed clinical symptoms since then. Steinfeld et al. (2009) reported a third girl with this disorder from a small Italian village. At age 5 years, she was severely handicapped, mentally retarded, and suffered from frequent epileptic seizures, at which point she was diagnosed as having cerebral folate transport deficiency. After oral folate treatment, her clinical condition slowly improved. CSF methyltetrahydrofolate (MTHF) concentrations were severely decreased in all 3 patients, and increased during folinic acid treatment. Brain MRI of the 2 severely affected patients showed severely disturbed myelination affecting the periventricular and subcortical white matter. Brain MRS showed decreased choline and inositol peaks in the parietooccipital white matter. The younger sister of the German boy had similar but milder abnormalities that normalized after treatment.

Molecular Genetics

In 2 German sibs with neurodegeneration due to cerebral folate transport deficiency, Steinfeld et al. (2009) identified compound heterozygosity for 2 mutations in the FOLR1 gene (Q118X; 136430.0001 and C175X; 136430.0002). An unrelated Italian girl with the disorder was homozygous for an 18-bp duplication (136430.0003) in the FOLR1 gene.