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Cerebral Folate Deficiency
Cerebral folate deficiency (CFD) can be defined as any neurological syndrome associated with low cerebrospinal fluid (CSF) 5-methyltetrahydrofolate (5MTHF), the active folate metabolite, in the presence of normal folate metabolism outside the nervous system. CFD could result from either disturbed folate transport or from increased folate turnover within the central nervous system (CNS).This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Cerebral folate deficiency is different from systemic folate deficiency in that the serum or plasma blood levels of folate are normal, but a sample of cerebral spinal fluid indicates decreased levels of folate. The form of folate in the blood and brain is predominately 5-methyltetrahydrofolate (5-MeTHF). This is critical because the concentration of 5-MeTHF in the cerebral spinal fluid is normally three to four times the concentration in plasma.The prevalence of cerebral folate transport deficiency is unknown. Fewer than 20 affected individuals have been described in the scientific literature.

Symptoms
Infantile-onset cerebral folate deficiency is a neurological syndrome that develops four to six months after birth. Its major manifestations are marked irritability, slow head growth, psychomotor retardation, cerebellar ataxia, pyramidal tract signs in the legs, dyskinesias (e.g., choreoathetosis and ballismus), and in some cases, seizures.After the age of three years, central visual disturbances can become manifest and lead to optic atrophy and blindness. The only identifiable biochemical abnormality consistently found in these children is a low level of 5MTHF in the cerebrospinal fluid. Weight loss and loss of appetite can occur, together with headaches, weakness, irritability, heart palpitations, sore tongue and behavioral disorders. Adults can also experience anemia, which may indicate advanced folate deficiency. Growth rate may be affected with children who suffer from folate deficiency, while pregnant women who have folate deficiency may give birth to infants with neural tube defects and low birth weight. Considering that some symptoms can be a result of other medical conditions, it is important to meet with a physician who will evaluate all the symptoms and provide proper medical care.Low levels of folate can also lead to depression because the normal formation of neurotransmitters, like serotonin, is hindered. Transmethylation reaction can also be disrupted, which leads to impaired metabolism of the myelin sheath, phospholipids and receptors.Conditions related to cerebral folate deficiency Cerebral folate deficiency and autism spectrum disorders.The early-onset low functioning autism with neurological deficits is characteristic of children with both autism and CFD. Interestingly, Rett syndrome, a disorder considered to be a part of the diagnostic group of autism spectrum disorders, has also been reported to have reduced 5-MTHF levels in the cerebrospinal fluid. It should be noted that only some children with autism who have CFD have been reported to possess FR1 autoantibodies.Because these reports of children with idiopathic autism and Rett syndrome include children with and without the FR1 autoantibody, this suggests that factors other than the FR1 autoantibody might be important for the development of CFD in these children. Although not speci!cally investigated, it is possible that many children with CFD and idiopathic autism or Rett syndrome who do not have the FR1 autoantibody may have mitochondrial disease. Indeed, as previously noted, mitochondrial disease appears to be associated with CFD, and there appears to be an increased prevalence of mitochondrial disease in children with idiopathic autism as compared to the general population. At least one case series has linked children with mitochondrial disease and regressive-type autism to CFD.9 Interestingly, Rett syndrome has also been linked to mitochondrial abnormalities in both an animal model and a case report. To a lesser extent, children with idiopathic autism might also manifest dysfunction of the mitochondria without necessarily fulfilling the criteria for strictly de!ned mitochondrial disease, it is possible that mitochondrial dysfunction could contribute to the development of CFD in children with idiopathic autism.

Diagnosis and Management
Molecular Genetics Tests Folic acid test Folic acid is a type of B vitamin. This article discusses the test to measure the amount of folic acid in the blood. The normal range is 2.7 to 17.0 nanograms per milliliter (ng/mL) or 6.12 to 38.52 nanomoles per liter (nmol/L).
 * Deletion/duplication analysis
 * Sequence analysis of select exons
 * Sequence analysis of the entire coding region
 * Linkage analysis
 * Targeted variant analysis

Oral treatment with 5-formyltetrahydrofolate (folinic acid) should be started in low doses at 0.5-1mg/kg/day, but in some patients higher daily doses of folinic acid at 2-3 mg/kg/day are required to normalize CSF 5MTHF values.