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Cerebral folate deficiency …
- Updated 04.30.2024
- Released 10.16.2012
- Expires For CME 04.30.2027
Cerebral folate deficiency
Introduction
Overview
Cerebral folate deficiency is characterized by decreased cerebral concentrations of 5-methyltetrahydrofolate in the presence of normal blood folate concentrations within the reference range. Patients may have developmental delay or regression, hypotonia, seizures, visual disturbances, and autistic features. Therapy with oral folinic acid is effective for treating many aspects of the disorder. The disorder is caused by decreased folate transport across the blood-brain barrier due to decreased function of folate receptor alpha. In some individuals, the disorder may be caused by autoantibodies directed against folate receptor alpha; in others, mutations in the FOLR1 gene, which encodes folate receptor alpha, have been identified.
Key points
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• Cerebral folate deficiency may be caused by decreased ability to transport folate across the blood-brain barrier because of decreased function of folate receptor alpha or due to specific disorders of folate metabolism. | |
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• Cerebral folate deficiency due to folate transport disorders can be caused by blocking autoantibodies against folate receptor alpha or mutations in the FOLR1 gene. | |
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• Affected individuals with cerebral folate deficiency due to mutations in the FOLR1 gene are normal at birth, but usually in the first year of life, these children exhibit deceleration of head growth and developmental delay or regression, usually in the first year of life. |
Historical note and terminology
Neurologic disease was first linked to folate deficiency in 1973 (46), and low CSF folate levels were first reported in 1981 (06). Cerebral folate deficiency was first reported by Ramaekers and colleagues in 2002 (39). As originally defined in 2004 by Ramaekers and Blau, cerebral folate deficiency is characterized by extremely low concentrations of 5-methyltetrahydrofolate (MTHF), the predominant circulating form of folate, in the cerebrospinal fluid in the presence of normal blood folate concentrations (37; 25).
The term “cerebral folate deficiency” is also sometimes used to describe conditions where CSF MTHF is low, in the presence of low or undefined peripheral folate levels (33), although this muddies the concepts and is confusing.
The term “idiopathic cerebral folate deficiency” had been suggested to differentiate it from cerebral folate deficiency that can develop in disorders such as Rett syndrome or Kearns-Sayre syndrome (37); however, because the etiology is known, the “idiopathic” descriptor seems inappropriate. More recent categorizations of disorders of folate metabolism have classified cerebral folate deficiency into primary and secondary forms (33).
Primary causes of cerebral folate deficiency include various inborn errors of metabolism:
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• Folate receptor alpha (FRα) deficiency |
Secondary causes of cerebral folate deficiency include a diverse collection of disorders, for many of which the precise metabolic disruption remains obscure:
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• Antibodies to folate receptor alpha |
Secondary cerebral folate deficiency in adults, when defined simply as low MTHF concentrations in the CSF (in the presence of undefined peripheral folate levels), is a heterogeneous but potentially treatable condition (24). Cerebral folate deficiency in adults should be considered in patients with mitochondrial diseases, primary brain calcifications, and unexplained complex neurologic disorders, especially if associated with white matter abnormalities (24).
Disorders that produce low CSF 5-MTHF and low peripheral total folate include the following conditions:
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• Nutritional deficiency of folate |
This article will address the primary causes of cerebral folate deficiency and the disorder resulting from antibodies to the folate receptor. Collectively, these conditions include metabolic recycling defects and disorders of folate transport that typically present with extremely low cerebrospinal fluid concentrations of 5-MTHF below 10 nmol/L prior to treatment.
Clinical manifestations
Presentation and course
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• Cerebral folate deficiency can be produced by a specific transport defect resulting in decreased transport of folate across the blood-brain barrier at the choroid plexus; this may be caused either by folate receptor alpha deficiency resulting from mutations of the FOLR1 encoding gene with an autosomal-recessive pattern of transmission or by the production of blocking/binding autoantibodies. | |
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• In most cases, folate receptor alpha deficiency presents as an encephalopathy during the first year of life after an initial period of normal motor development. | |
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• Patients with cerebral folate deficiency associated with blocking autoantibodies against folate receptor alpha may present at a later age with autism or schizophrenia, which is unresponsive to conventional treatment. | |
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• Methylenetetrahydrofolate reductase deficiency, the most frequent inborn error of folate metabolism, has a wide phenotypic spectrum ranging from severe neurologic deterioration and early death in infancy to asymptomatic adults. | |
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• Clinical signs of dihydrofolate reductase deficiency include severe megaloblastic anemia or pancytopenia, microcephaly (and cerebral and cerebellar atrophy), and refractory seizures. | |
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• Clinical signs of methenyl-tetrahydrofolate synthase deficiency include microcephaly, epilepsy, and hypomyelination. |
Folate transport disorders. Cerebral folate deficiency can be produced by a specific transport defect resulting in decreased folate transport across the blood-brain barrier at the choroid plexus. This may be caused either by folate receptor alpha deficiency resulting from mutations of the FOLR1 encoding gene with an autosomal-recessive transmission pattern or by the production of blocking/binding autoantibodies.
Patients with genetic forms of cerebral folate deficiency typically present with developmental delay, seizures, abnormal movements, and delayed myelination (30; 34).
Age of clinical onset of folate receptor alpha deficiency varies, but in most cases, the disorder presents as an encephalopathy during the first year of life after an initial period of normal motor development (50). Early signs of the disorder may include agitation and sleep disturbances. Affected individuals show deceleration of head growth and psychomotor delay or regression that can develop into severe retardation in the absence of treatment. Hypotonia, dyskinesia, spasticity, and ataxia may be present (31; 14). There may also be visual disturbances leading to visual loss and optic atrophy in the absence of treatment, and some children exhibit progressive hearing loss starting at about 6 years of age. Seizures (ie, myoclonic, tonic, astatic, generalized tonic-clonic) are typical, with myoclonic seizures being the most frequent seizure type; these may be intractable (37; 18; 28; 05; 27; 50; 13; 17; 43; 51; 14; 22; 25; 23; 20). Infantile spasms and status epilepticus have also been reported (49). Several children have had autistic features (28; 27; 15; 35; 20). On neuroimaging, untreated children have shown moderate frontotemporal atrophy with signs of periventricular and subcortical demyelination or hypomyelination and slowly progressive supra- and infratentorial atrophy (37; 22). A peripheral neuropathy with axonal degeneration and demyelinating features has also been reported (22).
Patients with cerebral folate deficiency associated with blocking autoantibodies against folate receptor alpha may present at a later age with autism or schizophrenia that is unresponsive to conventional treatment (41; 38; 45; 44; 19; 12; 35; 32) or with myoclonus and memory impairment (48). A 13-year-old previously healthy boy presented with a 17-month history of schizophrenic symptoms with progressively worsening catatonia, near-complete mutism, frequent enuresis and encopresis, and severe psychomotor retardation (19). A 58-year-old woman with folate receptor alpha autoimmunity presented with mild myoclonus and short-term memory impairment (48).
Patients with genetic forms of cerebral folate deficiency may present with other genetic disorders in nearby areas on chromosome 11. For example, a boy presented with congenital deafness, hypotonia, and ataxia in early childhood (13). At age 6, he developed intractable epilepsy. He deteriorated clinically, and at age 8 he developed respiratory arrest and severe hypercapnia. He had homozygous nonsense mutations in the FOLR1 gene and FGF3 gene, both of which map to 11q13. The latter mutation caused congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome).
Disorders of folate metabolism. Methylenetetrahydrofolate reductase deficiency is the most frequent inborn error of folate metabolism, with more than 200 patients reported in the literature (07; 33). The wide phenotypic spectrum ranges from severe neurologic deterioration and early death in infancy to asymptomatic adults. Hematological signs include megaloblastic anemia or pancytopenia. Neurologic presentations of severe methylenetetrahydrofolate deficiency include early-onset cases presenting in the first months of life with intractable seizures, epileptic encephalopathy, apnea, and hydrocephalus, and later-onset cases presenting with neurologic regression, ataxia, seizures, cerebral atrophy, and delayed myelination (33). Clinical manifestations in older children and adults include intellectual disability, recurrent cerebrovascular occlusion, psychiatric manifestations, and cerebral white matter abnormalities.
Clinical signs of dihydrofolate reductase deficiency include severe megaloblastic anemia or pancytopenia, microcephaly (and cerebral and cerebellar atrophy), and refractory seizures (04; 09; 33).
Clinical signs of methenyl-tetrahydrofolate synthase deficiency include microcephaly, epilepsy, and hypomyelination (47; 33).
Prognosis and complications
Prognosis and complications vary across the disorders of folate transport and metabolism.
Biological basis
Etiology and pathogenesis
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• Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. | |
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• Humans and other mammals cannot synthesize folate and depend on dietary sources to maintain normal levels. | |
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• Cerebral folate deficiency can result from decreased function of folate receptor alpha, which, together with the proton-coupled folate receptor, is required for transport of folate (mainly as MTHF) across the blood-brain barrier at the choroid plexus. | |
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• Two causes of cerebral folate deficiency have been identified: some patients have an autosomal recessive disorder resulting from mutations in the FOLR1 gene, which encodes folate receptor alpha, whereas others have blocking autoantibodies directed against folate receptor alpha. | |
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• The fundamental characteristic of these disorders is a specific inability to transport folate from the blood to the central nervous system, resulting in decreased CSF MTHF concentrations in the presence of normal blood folate concentrations. | |
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• Methylenetetrahydrofolate reductase deficiency is an autosomal recessive disorder caused by mutations in the MTHFR gene on chromosome 1. | |
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• Dihydrofolate reductase deficiency is an autosomal recessive disorder caused by a homozygous mutation in the DHFR gene on chromosome 5q. | |
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• Methenyltetrahydrofolate synthetase deficiency is an autosomal recessive disorder caused by mutations in the MTHFS gene on chromosome 15. |
Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Humans and other mammals cannot synthesize folate and depend on dietary sources to maintain normal levels (03).
Folate transport disorders. Cerebral folate deficiency can result from decreased function of folate receptor alpha, which, together with the proton-coupled folate receptor, is required for transport of folate (mainly as MTHF) across the blood-brain barrier at the choroid plexus (54; 02; 53; 33).
Folic acid metabolism and 5-MTHF transport across the choroid plexus epithelium in the brain
Red arrows and red crosses indicate the alternative pathway induced by FRα deficiency. Blue arrows indicate effects of folinic acid treatment. Legend: 5MTHF: 5-methylenetetrahydrofolate; B6: vitamin B6; B12: vitamin B12; CSF: c...
Two causes have been identified: some patients have an autosomal recessive disorder resulting from mutations in the FOLR1 gene, which encodes folate receptor alpha (50; 17); other patients have blocking autoantibodies directed against folate receptor alpha (41; 05; 40).
The fundamental characteristic of these disorders is a specific inability to transport folate from the blood to the central nervous system, resulting in decreased CSF MTHF concentrations in the presence of normal blood folate concentrations. This contrasts with hereditary folate malabsorption or dietary folate deficiency where both blood and CSF folate concentrations are decreased (53). Antibodies against folate receptor alpha may play a role in cerebral folate deficiency in individuals with Rett syndrome and a form of Aicardi-Goutieres syndrome (43).
Mutations in the FOLR1 gene on chromosome 11q13.4 have been identified in more than 20 families (33).
To date, various mutations have been identified, including nonsense, missense, splice-site mutations, and insertion mutations (08; 50; 31; 13; 29; 17; 01).
Disorders of folate metabolism.
Methylenetetrahydrofolate reductase deficiency is an autosomal recessive disorder caused by mutations in the MTHFR gene on chromosome 1. The cytogenetic location of the MTHFR gene is 1p36.22.
MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the essential methyl group donor for remethylation of homocysteine to methionine (so consequently, key biochemical changes associated with this disorder include elevated plasma total homocysteine and low methionine levels) (52).
Interaction of folate cycling with the remethylation of homocysteine to methionine
Folate metabolism. The interaction of folate cycling with the remethylation of homocysteine to methionine under the action of methionine synthase. Vitamin B12 is an additional cofactor for this reaction. Abbreviations (in alphabet...
Dihydrofolate reductase deficiency is an autosomal recessive disorder caused by homozygous mutation in the DHFR gene on chromosome 5q. The cytogenetic location of the DHFR gene is 5q14.1.
DHFR converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for de novo synthesis of purines, thymidylic acid, and some amino acids.
Methenyltetrahydrofolate synthetase deficiency is an autosomal recessive disorder caused by mutations in the MTHFS gene on chromosome 15. The cytogenetic location of the DHFR gene is 15q25.1.
5,10-MTHFS catalyzes the ATP-dependent conversion of folinic acid (5-formyltetrahydrofolate, 5-FTHF) to 5,10-methenyltetrahydrofolate (5,10-MTHF) (10). 5,10-methenyltetrahydrofolate is then converted to either 5,10-methylene-tetrahydrofolate, the precursor of 5-MTHF, or 10-formyltetrahydrofolate, which is important for purine metabolism.
Epidemiology
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• Prevalence of cerebral folate deficiency is estimated to be between 1 in 4000 and 1 in 6000 children, although the disorder is probably underdiagnosed. | |
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• Methylenetetrahydrofolate reductase deficiency is the most frequent inborn error of folate metabolism. Other inborn disorders of folate metabolism are rare. |
Prevalence of cerebral folate deficiency is estimated to be between 1/4000 and 1/6000 children, although the disorder is probably underdiagnosed (43). More than 20 affected children have been reported with FOLR1 mutations (33). Methylenetetrahydrofolate reductase deficiency is the most frequent inborn error of folate metabolism, with more than 200 patients reported in the literature (07; 33). Dihydrofolate reductase deficiency appears to be very rare: six individuals were described from three families in 2011, but no cases have been reported since then (04; 09; 33). Two unrelated boys have been reported with methenyltetrahydrofolate synthetase deficiency (47).
Prevention
Prevention is not possible; early diagnosis before development of severe neurologic problems appears vital.
Differential diagnosis
Confusing conditions
Cerebral folate deficiency is characterized by decreased folate (MTHF) concentration in the CSF (less than 40 nmol/L) in the presence of normal blood folate concentrations. Cerebral folate deficiency from cerebral folate transport defects can be confirmed by identifying antibodies to folate receptor alpha (although this test is not commonly available) or by detecting mutations in FOLR1. Cerebral folate concentrations are extremely low (less than 5 nmol/L) in individuals with FOLR1 mutations (17; 33).
Decreased concentrations of folate in the CSF also may be seen in several other neurologic disorders, including with Rett syndrome, Aicardi-Goutières syndrome, 3-phosphoglcerate dehydrogenase deficiency, dihydropteridine reductase deficiency, aromatic amino acid decarboxylase deficiency, Kearns-Sayre syndrome, and mitochondrial complex I encephalomyopathy, as well as with chronic exposure to antifolate drugs or anticonvulsant medications (37; 36).
Diagnostic workup
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• Diagnostic procedures are required to establish the diagnosis of cerebral folate deficiency and rule out alternatives, including measurement of folate in blood and Identification of decreased MTHF concentrations in CSF (less than 40 nmol/L), followed by a series of studies to evaluate possible causes of decreased cerebral MTHF concentrations with normal blood folate concentrations. | |
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• On magnetic resonance spectroscopy, neuroradiological findings in patients with cerebral folate deficiency may include delayed myelination, cerebellar atrophy, bilateral basal ganglia calcifications, and decreased choline and inositol peaks. |
Early diagnosis is crucial because high-dose folinic acid is an effective treatment that can ameliorate or even prevent further neurodegeneration (14).
The following diagnostic procedures are required to establish the diagnosis of cerebral folate deficiency and rule out alternatives:
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• Measurement of folate in blood. Decreased folate concentrations in blood indicate a dietary deficiency of folate or folate malabsorption; this can be caused by disorders affecting the gut, for example, celiac disease, or mutations in the SLC46A1 gene encoding the proton-coupled folate transporter, PCFT; loss of function, of which can cause hereditary folate malabsorption (16). | ||
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• Identification of decreased MTHF concentrations in CSF (less than 40 nmol/L). | ||
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• Evaluation of possible causes of decreased cerebral MTHF concentrations with normal blood folate concentrations: | ||
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- Methylenetetrahydrofolate reductase (MTHFR) deficiency: differentiated from cerebral folate deficiency due to decreased function of folate receptor alpha by elevated plasma homocysteine and decreased methionine concentrations; confirmed by enzymatic assay or identification of mutations in the MTHFR gene. CSF 5-MTHF levels are generally very low (< 10 nmol/L). Other key biochemical abnormalities include elevated plasma total homocysteine and low methionine levels. | ||
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- Dihydrofolate reductase (DHFR) deficiency: differentiated from cerebral folate deficiency due to decreased function of folate receptor alpha by the presence of megaloblastic anemia or pancytopenia; confirmed by enzymatic assay or by identification of mutations in the DHFR gene. CSF 5-MTHF levels are generally very low (< 10 nmol/L). Other key biochemical changes include low CSF tetrahydrobiopterin (BH4) and low/normal CSF monoamine metabolites. Peripheral biomarkers (ie, folate, cobalamin, and homocysteine) are normal (04; 09; 33). | ||
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- Methenyl-tetrahydrofolate synthase deficiency: CSF 5-MTHF levels are generally low-normal; confirmed by identification of mutations in the MTHFS gene. | ||
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- Kearns-Sayre syndrome, Rett syndrome, Aicardi-Goutières syndrome, 3-phosphoglcerate dehydrogenase deficiency, dihydropteridine reductase deficiency, aromatic amino acid decarboxylase deficiency, and mitochondrial complex I encephalomyopathy represent other rare potential secondary causes of decreased cerebral folate. | ||
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• Test for presence of autoantibodies to folate receptor alpha or FOLR1 mutations. | ||
Neuroradiological findings in patients with cerebral folate deficiency may include delayed myelination, diffuse white matter abnormalities, cerebellar atrophy, bilateral basal ganglia calcifications, and decreased choline and inositol peaks on magnetic resonance spectroscopy (36; 25; 23).
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Diffuse white matter abnormalities in girl with cerebral folate deficiency (MRI)
Brain MRI performed in girl at 4 and 12 years old shows diffuse white matter abnormalities linked to hypomyelination. MRI with FLAIR (A–C, G–I) and T2 (D–F, J–L) sequences. Red arrows show diffuse white matter abnormalities lin...
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Diffuse white matter abnormalities and subsequent improvement with folinic acid treatment (MRI)
(A) T2-weighted coronal MRI showing abnormal high signal sparing the subcortical white matter with slightly periventricular location at age 8 years before folinic acid treatment. (B) T2-weighted coronal MRI showing improvement ...
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Basal ganglia calcifications and diffuse white abnormalities in child with cerebral folate deficiency (CT)
Cerebral CT-scan in 4-year-old child. Red arrows show brain calcifications of the globus pallidus (A) and diffuse white matter abnormalities (B). (Source: Mafi S, Laroche-Raynaud C, et al. Pharmacoresistant epilepsy in childhoo...
Management
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• The most effective treatment of cerebral folate deficiency due to folate transport disorders has been oral 5-formyltetrahydrofolate, a 5-formyl derivative of tetrahydrofolic acid, which has been given the generic names of folinic acid (British-approved name) or leucovorin (United states-adopted name). | |
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• Treatment with folic acid is ineffective and may instead result in worsening seizures. | |
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• A milk-free diet may be helpful for cerebral folate deficiency due to FOLR1 blocking or binding autoantibodies because this may help downregulate the production of FOLR1 autoantibodies. | |
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• Treatment of methylenetetrahydrofolate reductase deficiency is with betaine, folinic acid, or 5-methyltetrahydrofolate. | |
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• The small number of reported cases of dihydrofolate reductase deficiency improved with oral folinic acid supplementation. | |
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• Treatment of methenyl-tetrahydrofolate synthase deficiency is with 5-methyltetrahydrofolate and intramuscular methylcobalamin. |
Folate transport disorders. The most effective treatment of cerebral folate deficiency due to folate transport disorders has been oral 5-formyltetrahydrofolate, a 5-formyl derivative of tetrahydrofolic acid, which has been given the generic names of folinic acid (British-approved name) or leucovorin (United states-adopted name).
5-formyltetrahydrofolate is generally administered as calcium or sodium salt (eg, calcium folinate, sodium folinate, leucovorin calcium, leucovorin sodium). Treatment has been initiated with 0.5 to 1.0 mg/kg per day and in some cases has been increased to as high as 5 mg/kg per day. Treatment results in the normalization of folate concentrations in CSF and improvement of neurologic findings, even in patients with severe cerebral folate deficiency (39; 18; 31; 01; 45; 26; 21; 22; 24; 34). Treatment with 5-formyltetrahydrofolate (folinic acid; leucovorin) can result in clinical improvement, but intravenous administration high-dose 5-formyltetrahydrofolate (folinic acid; leucovorin) may be necessary to control seizures and stop neurologic regression (11). In some cases, early treatment initiation with oral folinic acid alone can result in complete neurologic recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency (34).
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Neurologic recovery with oral folinic acid in patient with cerebral folate deficiency (1)
Brain MRI of a patient with cerebral folate deficiency from age 2 to 12 years. T2-weighted images are shown at 2 years (column 1: A1-E1), 5 years (column 2: A2-E2), 7 years (column 3: A3-E3), 10 years (column 4: A4-E4), and 12 ...
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Neurologic recovery with oral folinic acid in patient with cerebral folate deficiency (2)
Brain MRI of a patient with cerebral folate deficiency from age 2 to 6 years. T2-weighted images are shown at 2 years (column 1: A1-E1), 3 years (column 2: A2-E2), 4 years (column 3: A3-E3), and 6 years (column 4: A4-E4). Sagit...
Treatment with folic acid is ineffective and may instead result in worsening seizures (42; 17; 49; 25).
A milk-free diet may be helpful for cerebral folate deficiency due to FOLR1 blocking or binding autoantibodies because this may help downregulate the production of FOLR1 autoantibodies (42).
Disorders of folate metabolism. Methylenetetrahydrofolate reductase deficiency is treated with betaine, folinic acid, or 5-methyltetrahydrofolate (33).
The small number of reported cases of dihydrofolate reductase deficiency improved with oral folinic acid supplementation, as demonstrated by improvement of CSF 5-MTHF levels, and improved seizure control and other neurologic symptoms (04; 09; 33).
Methenyl-tetrahydrofolate synthase deficiency is treated with 5-methyltetrahydrofolate and intramuscular methylcobalamin (33).
Outcomes
Individuals with cerebral folate deficiency due to folate transport disorders have usually responded to therapy with oral 5-formyltetrahydrofolate (folinic acid, leucovorin), a stable reduced folate derivative. It is probably critical to commence treatment before serious neurologic problems, such as developmental delay or visual and hearing loss, become established because they may not be readily reversible. In some cases, intravenous administration of high-dose 5-formyltetrahydrofolate (folinic acid; leucovorin) may be necessary to control seizures and stop neurologic regression (11).
Media
References
- 01
- Al-Baradie RS, Chaudhary MW. Diagnosis and management of cerebral folate deficiency. A form of folinic acid-responsive seizures. Neurosciences (Riyadh) 2014;19(4):312-6. PMID 25274592
- 02
- Alam C, Hoque MT, Finnell RH, Goldman ID, Bendayan R. Regulation of reduced folate carrier (RFC) by vitamin D receptor at the blood-brain barrier. Mol Pharm 2017;14(11):3848-58. PMID 28885847
- 03
- Alam C, Kondo M, O'Connor DL, Bendayan R. Clinical implications of folate transport in the central nervous system. Trends Pharmacol Sci 2020;41(5):349-61. PMID 32200980
- 04
- Banka S, Blom HJ, Walter J, et al. Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency. Am J Hum Genet 2011;88(2):216-25. PMID 21310276
- 05
- Bonkowsky JL, Ramaekers VT, Quadros EV, Lloyd M. Progressive encephalopathy in a child with cerebral folate deficiency syndrome. J Child Neurol 2008;23:1460-3. PMID 18854521
- 06
- Botez MI, Bachevalier J. The blood-brain barrier and folate deficiency. Am J Clin Nutr 1981;34(9):1725-30. PMID 7282600
- 07
- Burda P, Schäfer A, Suormala T, et al. Insights into severe 5,10-methylenetetrahydrofolate reductase deficiency: molecular genetic and enzymatic characterization of 76 patients. Hum Mutat 2015;36(6):611-21. PMID 25736335
- 08
- Cario H, Bode H, Debatin KM, Opladen T, Schwarz K. Congenital null mutations of the FOLR1 gene; a progressive neurologic disease and its treatment. Neurology 2009;73:2127-9. PMID 20018644
- 09
- Cario H, Smith DE, Blom H, et al. Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease. Am J Hum Genet 2011;88(2):226-31. PMID 21310277
- 10
- Dayan A, Bertrand R, Beauchemin M, et al. Cloning and characterization of the human 5,10-methenyltetrahydrofolate synthetase-encoding cDNA. Gene 1995;165(2):307-11. PMID 8522195
- 11
- Delmelle F, Thöny B, Clapuyt P, Blau N, Nassogne MC. Neurological improvement following intravenous high-dose folinic acid for cerebral folate transporter deficiency caused by FOLR-1 mutation. Eur J Paediatr Neurol 2016;20(5):709-13. PMID 27328863
- 12
- Desai A, Sequeira JM, Quadros EV. The metabolic basis for developmental disorders due to defective folate transport. Biochimie 2016;126:31-42. PMID 26924398
- 13
- Dill P, Schneider J, Weber P, et al. Pyridoxal phosphate-responsive seizures in a patient with cerebral folate deficiency (CFD) and congenital deafness with labyrinthine aplasia, microtia and microdontia (LAMM). Mol Genet Metab 2011;104:362-8. PMID 21752681
- 14
- Ferreira P, Luco SM, Sawyer SL, Davila J, Boycott KM, Dyment DA. Late diagnosis of cerebral folate deficiency: fewer seizures with folinic acid in adult siblings. Neurol Genet 2015;2(1):e38. PMID 27066576
- 15
- Frye RE. Metabolic and mitochondrial disorders associated with epilepsy in children with autism spectrum disorder. Epilepsy Behav 2015;47:147-57. PMID 25440829
- 16
- Goldman ID, Adam MP, Feldman J, et al. Hereditary folate malabsorption. In: GeneReviews [Internet]. Seattle: University of Washington, 1993. Accessed May 2024.
- 17
- Grapp M, Just IA, Linnankivi T, et al. Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency. Brain 2012;135:2022-31. PMID 22586289
- 18
- Hansen FJ, Blau N. Cerebral folate deficiency: life-changing supplementation with folinic acid. Molec Genet Metab 2005;84:371-3. PMID 15781200
- 19
- Ho A, Michelson D, Aaen G, Ashwal S. Cerebral folate deficiency presenting as adolescent catatonic schizophrenia: a case report. J Child Neurol 2010;25:898-900. PMID 20445197
- 20
- Kanmaz S, Simsek E, Yilmaz S, Durmaz A, Serin HM, Gokben S. Cerebral folate transporter deficiency: a potentially treatable neurometabolic disorder. Acta Neurol Belg 2023;123(1):121-7. PMID 34002331
- 21
- Karin I, Borggraefe I, Catarino CB, et al. Folinic acid therapy in cerebral folate deficiency: marked improvement in an adult patient. J Neurol 2017;264(3):578-82. PMID 28054128
- 22
- Kobayashi Y, Tohyama J, Akiyama T, et al. Severe leukoencephalopathy with cortical involvement and peripheral neuropathy due to FOLR1 deficiency. Brain Dev 2017;39(3):266-70. PMID 27743887
- 23
- Mafi S, Laroche-Raynaud C, Chazelas P, et al. Pharmacoresistant epilepsy in childhood: think of the cerebral folate deficiency, a treatable disease. Brain Sci 2020;10(11):762. PMID 33105619
- 24
- Masingue M, Benoist JF, Roze E, et al. Cerebral folate deficiency in adults: a heterogeneous potentially treatable condition. J Neurol Sci 2019;396:112-8. PMID 30448717
- 25
- Mastrangelo M. Actual insights into treatable inborn errors of metabolism causing epilepsy. J Pediatr Neurosci 2018;13(1):13-23. PMID 29899766
- 26
- Molero-Luis M, Serrano M, O'Callaghan MM, et al. Clinical, etiological and therapeutic aspects of cerebral folate deficiency. Expert Rev Neurother 2015;15(7):793-802. PMID 26092490
- 27
- Moretti P, Peters SU, del Gaudio D, et al. Autistic symptoms, developmental regression, mental retardation, epilepsy, and dyskinesias in CNS folate deficiency. J Autism Dev Disord 2008;38:1170-7. PMID 18027081
- 28
- Moretti P, Sahoo T, Hyland K, et al. Cerebral folate deficiency with developmental delay, autism, and response to folinic acid. Neurology 2005;64:1088-90. PMID 15781839
- 29
- Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011;478:57-63. PMID 21937992
- 30
- Papadopoulou MT, Dalpa E, Portokalas M, et al. Cerebral folate deficiency in two siblings caused by biallelic variants including a novel mutation of FOLR1 gene: intrafamilial heterogeneity following early treatment and the role of ketogenic diet. JIMD Rep 2021;60(1):3-9. PMID 34258135
- 31
- Perez-Duenas B, Toma C, Ormazabal A, et al. Progressive ataxia and myoclonic epilepsy in a patient with a homozygous mutation in the FOLR1 gene. J Inher Metab Dis 2010;33:795-802. PMID 20857335
- 32
- Phunsawat P, Chiangjong W, Chutipongtanate S, et al. Folate receptor alpha autoantibodies in children with autism spectrum disorder. Biomarkers 2022;27(8):715-9. PMID 36112150
- 33
- Pope S, Artuch R, Heales S, Rahman S. Cerebral folate deficiency: Analytical tests and differential diagnosis. J Inherit Metab Dis 2019;42(4):655-72. PMID 30916789
- 34
- Potic A, Perrier S, Radovic T, et al. Hypomyelination caused by a novel homozygous pathogenic variant in FOLR1: complete clinical and radiological recovery with oral folinic acid therapy and review of the literature. Orphanet J Rare Dis 2023;18(1):187. PMID 37443037
- 35
- Quadros EV, Sequeira JM, Brown WT, et al. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res 2018;11(5):707-12. PMID 29394471
- 36
- Quijada-Fraile P, O'Callaghan M, Martín-Hernández E, et al. Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome. Orphanet J Rare Dis 2014;9:217. PMID 25539952
- 37
- Ramaekers VT, Blau N. Cerebral folate deficiency. Dev Med Child Neurol 2004;46:843-51. PMID 15581159
- 38
- Ramaekers VT, Blau N, Sequeira JM, Nassogne MC, Quadros E. Folate receptor autoimmunity and cerebral folate deficiency in low-functioning autism with neurological deficits. Neuropediatrics 2007;38(6):276-81. PMID 18461502
- 39
- Ramaekers VT, Häusler M, Opladen T, Heimann G, Blau N. Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution. Neuropediatrics 2002;33:301-8. PMID 12571785
- 40
- Ramaekers VT, Quadros EV. Cerebral folate deficiency syndrome: early diagnosis, intervention and treatment strategies. Nutrients 2022;14(15):3096. PMID 35956272
- 41
- Ramaekers VT, Rothenberg SP, Seqeira JM, et al. Autoantibodies to folate receptors in the cerebral folate deficiency syndrome. N Engl J Med 2005;352:1985-91. PMID 15888699
- 42
- Ramaekers VT, Sequeira JM, Blau N, Quadros EV. A milk-free diet downregulates folate receptor autoimmunity in cerebral folate deficiency syndrome. Dev Med Child Neurol 2008;50(5):346-52. PMID 18355335
- 43
- Ramaekers V, Sequeira JM, Quadros EV. Clinical recognition and aspects of the cerebral folate deficiency syndromes. Clin Chem Lab Med 2013;51:497-511. PMID 23314536
- 44
- Ramaekers VT, Sequeira JM, Quadros EV. The basis for folinic acid treatment in neuro-psychiatric disorders. Biochimie 2016;126:79-90. PMID 27068282
- 45
- Ramaekers VT, Thöny B, Sequeira JM, et al. Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies. Mol Genet Metab 2014;113(4):307-14. PMID 25456743
- 46
- Reynolds EH, Rothfeld P, Pincus JH. Neurological disease associated with folate deficiency. Br Med J 1973;2(5863):398-400. PMID 4703098
- 47
- Rodan LH, Qi W, Ducker GS, et al. 5,10-methenyltetrahydrofolate synthetase deficiency causes a neurometabolic disorder associated with microcephaly, epilepsy, and cerebral hypomyelination. Mol Genet Metab 2018;125(1-2):118-26. PMID 30031689
- 48
- Sadighi Z, Butler IJ, Koenig MK. Adult-onset cerebral folate deficiency. Arch Neurol 2012;69:778-9. PMID 22371854
- 49
- Steele SU, Cheah SM, Veerapandiyan A, Gallentine W, Smith EC, Mikati MA. Electroencephalographic and seizure manifestations in two patients with folate receptor autoimmune antibody-mediated primary cerebral folate deficiency. Epilepsy Behav 2012;24(4):507-12. PMID 22749608
- 50
- Steinfeld R, Grapp M, Kraetzner R, et al. Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism. Am J Hum Genet 2009;85:354-63. PMID 19732866
- 51
- Toelle SP, Wille D, Schmitt B, Scheer I, Thöny B, Plecko B. Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency. Epileptic Disord 2014;18:88-92. PMID 24556562
- 52
- Watkins D, Rosenblatt DS. Update and new concepts in vitamin responsive disorders of folate transport and metabolism. J Inherit Metab Dis 2012;35(4):665-70. PMID 22108709
- 53
- Zhao R, Aluri S, Goldman ID. The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: hereditary folate malabsorption. Mol Aspects Med 2017;53:57-72. PMID 27664775
- 54
- Zhao R, Min SH, Wang Y, Campanella E, Low PS, Goldman ID. A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis. J Biol Chem 2009;284:4267-74. PMID 19074442
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Douglas J Lanska MD MS MSPH
Dr. Lanska of the University of Wisconsin School of Medicine and Public Health and the Medical College of Wisconsin has no relevant financial relationships to disclose.
See Profile
Former Authors
- David Watkins PhD
- David S Rosenblatt MD
Patient Profile
- Age range of presentation
-
- 1 month to 64 years
- Sex preponderance
-
- male > female, >1:1
- Heredity
-
- heredity may be a factor
- autosomal recessive
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-11
-
- Other specified genetic epileptic syndromes with neonatal onset: 8A61.0Y
- Disorders of folate metabolism or transport: 5C63.1
- Other specified folate deficiency anaemia: 3A02.Y
- OMIM
-
- Neurodegeneration due to cerebral folate deficiency: #613068
- Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFR deficiency): #613839
- Folate-sensitive neural tube defects: #601634
- Methylenetetrahydrofolate reductase deficiency (MTHFR deficiency): #236250
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