levoleucovorin and Folic-Acid-Deficiency

Neurodegeneration due to cerebral folate transport deficiency is a rare autosomal recessive disorder caused by biallelic pathogenic variants in FOLR1. Onset typically occurs in late infancy and is characterized by psychomotor regression, epilepsy, and a hypomyelinating leukodystrophy on magnetic resonance imaging. If left untreated, progressive neurodegeneration occurs. However, early treatment with folinic acid has been shown to stabilize or reverse neurological features. Approximately thirty patients have been described worldwide. Here, we report the first two cases with genetically proven cerebral folate transport deficiency from South-Eastern Europe, describe the effect of oral folinic acid therapy on clinical and neuroradiological features and review the literature.. Two siblings presented in childhood with clinical and radiological findings consistent with a hypomyelinating leukodystrophy. Exome sequencing revealed a novel homozygous pathogenic variant in FOLR1 (c.465_466delinsTG; p.W156G), confirming the diagnosis of neurodegeneration due to cerebral folate transport deficiency. Folinic acid treatment was promptly initiated in both patients. The younger sibling was treated early in disease course at 2 years of age, and demonstrated complete recovery in clinical and MRI features. The older sibling, who was 8 years of age at the time of diagnosis and treatment, demonstrated partial but substantial improvements.. We present the first account in the literature that early treatment initiation with oral folinic acid alone can result in complete neurological recovery of both clinical and radiological abnormalities in neurodegeneration due to cerebral folate deficiency. Moreover, through the report of these patients along with review of the literature, we provide information about the natural history of the disease with comparison of treatment effects at different stages of disease progression. This report also reinforces the importance of universal access to genetic testing to ensure prompt diagnoses for treatable disorders.

Topics: Epilepsy; Folate Receptor 1; Folic Acid Deficiency; Humans; Leucovorin; Neuroaxonal Dystrophies

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that currently has no approved medical therapy to address core symptoms or underling pathophysiological processes. Several compounds are under development that address both underlying pathophysiological abnormalities and core ASD symptoms. This article reviews one of these treatments, d,l-leucovorin calcium (also known as folinic acid) for treatment of folate pathway abnormalities in children with ASD. Folate is a water-soluble B vitamin that is essential for normal neurodevelopment and abnormalities in the folate and related pathways have been identified in children with ASD. One of these abnormalities involves a partial blockage in the ability of folate to be transported into the brain utilizing the primary transport mechanism, the folate receptor alpha. Autoantibodies which interfere with the function of the folate receptor alpha called folate receptor alpha autoantibodies have been identified in 58%-76% of children with ASD and independent studies have demonstrated that blood titers of these autoantibodies correlate with folate levels in the cerebrospinal fluid. Most significantly, case-series, open-label, and single and double-blind placebo-controlled studies suggest that d,l-leucovorin, a reduced folate that can bypass the blockage at the folate receptor alpha by using the reduced folate carrier, an alternate pathway, can substantially improve particular symptoms in children with ASD, especially those positive for folate receptor alpha autoantibodies. This article reviews the current evidence for treating core and associated symptoms and underlying pathophysiological mechanisms in children with ASD with d,l-leucovorin.

Topics: Autism Spectrum Disorder; Autoantibodies; Child; Folate Receptor 1; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Vitamin B Complex

In the folate cycle MTHFD1, encoded by MTHFD1, is a trifunctional enzyme containing 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase activity. To date, only one patient with MTHFD1 deficiency, presenting with hyperhomocysteinemia, megaloblastic anaemia, hemolytic uremic syndrome (HUS) and severe combined immunodeficiency, has been identified (Watkins et al J Med Genet 48:590-2, 2011). We now describe four additional patients from two different families. The second patient presented with hyperhomocysteinemia, megaloblastic anaemia, HUS, microangiopathy and retinopathy; all except the retinopathy resolved after treatment with hydroxocobalamin, betaine and folinic acid. The third patient developed megaloblastic anaemia, infection, autoimmune disease and moderate liver fibrosis but not hyperhomocysteinemia, and was successfully treated with a regime that included and was eventually reduced to folic acid. The other two, elder siblings of the third patient, died at 9 weeks of age with megaloblastic anaemia, infection and severe acidosis and had MTFHD1 deficiency diagnosed retrospectively. We identified a missense mutation (c.806C > T, p.Thr296Ile) and a splice site mutation (c.1674G > A) leading to exon skipping in the second patient, while the other three harboured a missense mutation (c.146C > T, p.Ser49Phe) and a premature stop mutation (c.673G > T, p.Glu225*), all of which were novel. Patient fibroblast studies revealed severely reduced methionine formation from [(14)C]-formate, which did not increase in cobalamin supplemented culture medium but was responsive to folic and folinic acid. These additional cases increase the clinical spectrum of this intriguing defect, provide in vitro evidence of disturbed methionine synthesis and substantiate the effectiveness of folic or folinic acid treatment.

Topics: Anemia, Megaloblastic; Cells, Cultured; Fatal Outcome; Female; Folic Acid; Folic Acid Deficiency; Humans; Hyperhomocysteinemia; Infant; Infant, Newborn; Leucovorin; Male; Methylenetetrahydrofolate Dehydrogenase (NADP); Minor Histocompatibility Antigens; Severe Combined Immunodeficiency; Young Adult

Cellular folate metabolism is highly compartmentalized, with mitochondria folate transport and metabolism being distinct from the well-known cytosolic folate metabolism. There is evidence supporting the association between low folate status and mitochondrial DNA (mtDNA) instability, and cerebral folate deficiency is relatively frequent in mitochondrial disorders. Furthermore, folinic acid supplementation has been reported to be beneficial not only in some patients with mitochondrial disease, but also in patients with relatively common diseases where folate deficiency might be an important pathophysiological factor. In this review, we focus on the evidence that supports the potential involvement of impaired folate metabolism in the pathophysiology of mitochondrial disorders.

Topics: Animals; Biological Transport; DNA, Mitochondrial; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Mitochondria; Mitochondrial Diseases

1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5-methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency.

Topics: Animals; Dietary Supplements; Folic Acid; Folic Acid Deficiency; Food, Fortified; Humans; Leucovorin; Methylenetetrahydrofolate Reductase (NADPH2); Polymorphism, Genetic; Tetrahydrofolates

The use of two antidepressants from the initiation of treatment in major depressive disorder has been investigated in several recent studies and forms a paradigm shift in the pharmacotherapy of the condition. Several, but not all, trials have claimed improved response and remission rates with the combinations as opposed to monotherapy. The use of folate preparations (folic and folinic acid and l-meth-ylfolate) have shown effective augmentation of antidepressant response in a variety of controlled and open-label settings in patients with normo- and hypofolatemic status. Several recent trials using L-methylfolate, the active and more bioavailable form of folic acid, have shown promising adjunctive use with a well-tolerated adverse event profile.

Topics: Antidepressive Agents; Depressive Disorder, Major; Drug Therapy, Combination; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Tetrahydrofolates; Treatment Outcome

We characterized cerebral folate deficiency (CFD) as any neuro-psychiatric condition associated with low spinal fluid (CSF) N5-methyltetrahydrofolate (MTHF) but normal folate status outside the central nervous system (CNS). The commonest cause underlying CFD syndromes is the presence of serum autoantibodies of the blocking type directed against folate receptor-α (FRα) attached to the plasma-side of choroid plexus epithelial cells. Blocking FR antibodies inhibit MTHF transport across the choroid plexus. Serum titers of FR antibodies may fluctuate significantly over time. Less frequent causes of CFD are FOLR-1 mutations, mitochondrial disorders and inborn errors affecting folate metabolism. Maternal FR antibodies have been associated with neural tube defects while the presence of FR antibodies in either one or both parents increases the risk of an offspring with infantile autism. Recognizable CFD syndromes attributed to FR-antibodies in childhood are infantile-onset CFD presenting 4-6 months after birth, infantile autism with neurological deficits, and a spastic ataxic syndrome from the age of 1 year, while progressive dystonic or schizophrenic syndromes develop during adolescence. FR autoantibodies are frequently found in autism spectrum disorders, in an Aicardi-Goutières variant and in Rett syndrome. The heterogeneous phenotype of CFD syndromes might be determined by different ages of onset and periods when FR autoantibodies are generated with consequent CNS folate deficiency. Folate deficiency during various critical stages of fetal and infantile development affects structural and functional refinement of the brain. Awareness of CFD syndromes should lead to early detection, diagnosis and improved prognosis of these potentially treatable group of autoimmune and genetically determined conditions.

Topics: Autoantibodies; Folate Receptor 1; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Mitochondrial Diseases; Mutation

Over the past decade, a syndrome consisting of low folate values in the cerebrospinal fluid (CSF) has been described. The syndrome has been associated with both genetic and acquired conditions that affect folate transport and metabolism and can result in severe neurological disorders. There is a wide range of underlying pathophysiological mechanisms, but a common feature in most patients is a good clinical response to folate therapy, especially when the syndrome is diagnosed early. In this review, we focus our attention on the genetic diseases leading to profound cerebral folate deficiency (CFD) and review current clinical, metabolic and therapeutic approaches.

Topics: Betaine; Cerebral Cortex; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intestinal Absorption; Leucovorin; Nervous System Diseases; Tetrahydrofolates

Topics: Brain; Child, Preschool; Chromatography, High Pressure Liquid; Diagnosis, Differential; Folate Receptor 1; Folic Acid; Folic Acid Deficiency; Humans; Infant; Leucovorin; Malnutrition; Tetrahydrofolates

Cerebral folate deficiency (CFD) is defined as any neurological syndrome associated with a low cerebrospinal fluid (CSF) concentration of 5-methyltetrahydrofolate (5MTHF) in the presence of normal peripheral folate status. CFD has a wide clinical presentation, with reported signs and symptoms generally beginning at around 4 months of age with irritability and sleep disturbances. These can be followed by psychomotor retardation, dyskinesia, cerebellar ataxia and spastic diplegia. Other signs may include deceleration of head growth, visual disturbances and sensorineural hearing loss. Identification of CFD is achieved by determining 5MTHF concentration in CSF. Once identified, CFD can in many cases be treated by administering oral folinic acid. Supplementation with folic acid is contraindicated and, if used, may exacerbate the CSF 5MTHF deficiency. Generation of autoantibodies against the folate receptor required to transport 5MTHF into CSF and mutations in the folate receptor 1 (FOLR1) gene have been reported to be causes of CFD. However, other mechanisms are probably also involved, as CFD has been reported in Aicardi-Goutiere's and Rett syndromes and in mitochondriopathies. Several metabolic conditions and a number of widely used drugs can also lead to a decrease in the concentration of CSF 5MTHF, and these should be considered in the differential diagnosis if a low concentration of 5MTHF is found following CSF analysis.

Topics: Administration, Oral; Autoantibodies; Brain Diseases; Dietary Supplements; Folate Receptor 1; Folic Acid Deficiency; Folic Acid Transporters; Genetic Predisposition to Disease; Humans; Leucovorin; Mutation; Risk Factors; Tetrahydrofolates; Treatment Outcome

Supplementation with folate may help reduce depressive symptoms. Folate, a naturally occurring B vitamin, is needed in the brain for the synthesis of norepinephrine, serotonin, and dopamine. Three forms of folate are commonly used: folic acid, 5-methyltetrahydrofolate (5-MTHF) (also known as methylfolate and L-methylfolate), and folinic acid. Some forms may be more bioavailable than others in patients with a genetic polymorphism and in those who take particular medications or use alcohol. Folic acid augmentation in depressed patients may reduce residual symptoms. The 5-MTHF formulation indicated efficacy as adjunctive therapy or monotherapy in reducing depressive symptoms in patients with normal and low folate levels, improving cognitive function and reducing depressive symptoms in elderly patients with dementia and folate deficiency, and reducing depressive and somatic symptoms in patients with depression and alcoholism. Adjunctive folinic acid reduced depressive symptoms in patients who were partially responsive or nonresponsive to a selective serotonin reuptake inhibitor. Evidence for the efficacy of folate in improving cognitive symptoms is equivocal, but most studies used folic acid. Although the studies reviewed have limitations and, historically, concerns have been raised about the role of folate in increasing cancer risk, masking B(12) deficiency, and worsening depressive symptoms, folate is generally well tolerated, and 5-MTHF may be less likely to incur some of these risks. Several forms of folate appear to be safe and efficacious in some individuals with major depressive disorder, but more information is needed about dosage and populations most suited to folate therapy.

Topics: Aged; Chemistry, Pharmaceutical; Clinical Trials as Topic; Dementia; Depressive Disorder, Major; Dietary Supplements; Dosage Forms; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Tetrahydrofolates; Treatment Outcome

Toxicities related to low-dose weekly methotrexate are largely due to its antifolate properties. Preexisting folate deficiency is associated with methotrexate toxicity in some patients. At the onset of methotrexate therapy and throughout therapy, the physician should be vigilant regarding one or more nutrient deficiencies. A multivitamin and, where appropriate, specific daily folic acid supplements should be employed. The only regimen known presently (through controlled trials) to treat side effects is the low-dose folinic acid (leucovorin) protocol outlined herein. Folic acid may be helpful to treat mild gastrointestinal symptoms. Folinic acid supplementation should be considered prophylactically in those requiring methotrexate who are at increased risk of hepatic disease. Other possible factors besides methotrexate should always be considered with the onset of new patient complaints or laboratory abnormalities. Claims that folic acid therapy is safer and more convenient than folinic acid seem unwarranted when one reviews the literature carefully. Cost differences between folic acid supplementation and folinic acid supplementation have been exaggerated.

Topics: Antidotes; Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials as Topic; Drug Therapy, Combination; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate

Topics: Female; Folic Acid Deficiency; Humans; Leucovorin; Pregnancy; Pregnancy Complications

A trial was carried out of prophylaxis of folate deficiency in 105 acutely ill patients immediately following admission to an ICU with evaluation of folate status. These patients were fed either orally or by enteral or parenteral nutrition. Three groups were established regardless of the type of nutrition: - Group 1 received 5 mg/day parenteral folinic acid; - Group 2 received 50 mg/week parenteral folinic acid; - Group 3 received no parenteral folinic acid. Before treatment, 19% of the patients presented very low serum folate levels (less than 2.7 ng/ml). Two of them developed acute folate deficiency with severe hematological disturbances quite reversed with folinic acid. Folate levels were inversely correlated with the severity of the clinical status and were lower in septic and feverish patients. The effect of folinic acid administration was assessed after seven days of treatment: daily administration of 5 mg folinic acid appeared to be the best regimen with normalization of serum folate levels in all cases; results appeared to be better than with 50 mg once weekly. Oral and enteral administration of folate supplies considered to be physiological (300 micrograms/day folic acid) did not appear to be sufficient to normalize in all cases blood folate levels in these acutely ill patients.

Topics: Acute Disease; Administration, Oral; Adult; Aged; Analysis of Variance; Clinical Trials as Topic; Critical Care; Drug Administration Schedule; Drug Evaluation; Enteral Nutrition; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Middle Aged; Parenteral Nutrition; Prospective Studies; Random Allocation; Time Factors

In a rat model, following exposure to rat folate receptor alpha antibodies (FRαAb) during gestation, FRαAb accumulates in the placenta and the fetus and blocks folate transport to the fetal brain and produces behavioral deficits in the offspring. These deficits could be prevented with folinic acid. Therefore, we sought to evaluate folate transport to the brain in young rat pups and determine what effect FRαAb has on this process, to better understand the folate receptor autoimmune disorder associated with cerebral folate deficiency (CFD) in autism spectrum disorders (ASD). When injected intraperitoneally (IP), FRαAb localizes to the choroid plexus and blood vessels including the capillaries throughout the brain parenchyma. Biotin-tagged folic acid shows distribution in the white matter tracts in the cerebrum and cerebellum. Since these antibodies can block folate transport to the brain, we orally administered various folate forms to identify the form that is better-absorbed and transported to the brain and is most effective in restoring cerebral folate status in the presence of FRαAb. The three forms of folate, namely folic acid, D,L-folinic acid and levofolinate, are converted to methylfolate while L-methylfolate is absorbed as such and all are efficiently distributed to the brain. However, significantly higher folate concentration is seen in the cerebrum and cerebellum with levofolinate in the presence or absence of FRαAb. Our results in the rat model support testing levofolinate to treat CFD in children with ASD.

Topics: Animals; Antibodies; Brain; Female; Folate Receptor 1; Folic Acid; Folic Acid Deficiency; Leucovorin; Pregnancy; Rats

Cerebral folate deficiency (CFD) syndrome is a rare treatable neurometabolic disorder with low levels of the active form of folaten in cerebrospinal fluid (CSF) arising from different causes such as FOLR1 gene mutations or autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus. It is characterized by late infantile onset refractory seizures, ataxia, movement disorder, and unexplained global developmental delay. Here, we report a patient diagnosed with autistic spectrum disorder, followed by refractory myoclonic-atonic seizures, ataxia, and loss of motor skills over time. A homozygous missense (c.665A > G) mutation in FOLR1 gene and extremely low CSF 5-methyltetrahydrofolate level led to the diagnosis of CFD. Although she was initiated on combined oral and intravenous high doses of folinic acid treatment at 6 years of age, mild improvement was achieved in terms of epileptic seizures and motor skills. It is important that CFD should be kept in mind in cases with refractory myoclonic-atonic seizure and folinic acid treatment should be started as soon as possible.

Topics: Ataxia; Female; Folate Receptor 1; Folic Acid Deficiency; Humans; Leucovorin; Mutation

Topics: Female; Folic Acid Deficiency; Follow-Up Studies; Humans; Infant; Leucovorin; Malabsorption Syndromes

Topics: Cadherins; Child; Epileptic Syndromes; Female; Folic Acid Deficiency; Humans; Leucovorin; Pedigree; Protocadherins; Tetrahydrofolates; Treatment Outcome; Vitamin B Complex

Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism.. Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well.. One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.

Topics: Age of Onset; Cerebral Cortex; Child; Encephalomalacia; Exome Sequencing; Folate Receptor 1; Folic Acid Deficiency; Homozygote; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Seizures; Status Epilepticus; Tetrahydrofolates

Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective.. Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels.. Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved.. Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.

Topics: Folic Acid Deficiency; Humans; Infant; Injections, Intramuscular; Leucovorin; Malabsorption Syndromes; Male; Vitamin B Complex

Ultraviolet (UV) is an omnipresent environmental carcinogen transmitted by sunlight. Excessive UV irradiation has been correlated to an increased risk of skin cancers. UVB, the most mutagenic component among the three UV constituents, causes damage mainly through inducing DNA damage and oxidative stress. Therefore, strategies or nutrients that strengthen an individual's resistance to UV-inflicted harmful effects shall be beneficial. Folate is a water-soluble B vitamin essential for nucleotides biosynthesis, and also a strong biological antioxidant, hence a micronutrient with potential of modulating individual's vulnerability to UV exposure. In this study, we investigated the impact of folate status on UV sensitivity and the protective activity of folate supplementation using a zebrafish model. Elevated reactive oxygen species (ROS) level and morphological injury were observed in the larvae exposed to UVB, which were readily rescued by supplementing with folic acid, 5-formyltetrahydrofolate (5-CHO-THF) and N-acetyl-L-cysteine (NAC). The UVB-inflicted abnormalities and mortality were worsened in Tg(hsp:EGFP-γGH) larvae displaying folate deficiency. Intriguingly, only supplementation with 5-CHO-THF, as opposed to folic acid, offered significant and consistent protection against UVB-inflicted oxidative damage in the folate-deficient larvae. We concluded that the intrinsic folate status correlates with the vulnerability to UVB-induced damage in zebrafish larvae. In addition, 5-CHO-THF surpassed both folic acid and NAC in preventing UVB-inflicted oxidative stress and injury in our current experimental zebrafish model.

Topics: Acetylcysteine; Animals; Antioxidants; Dietary Supplements; Folic Acid Deficiency; Larva; Leucovorin; Oxidative Stress; Reactive Oxygen Species; Ultraviolet Rays; Vitamin B Complex; Zebrafish

Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system. Its manifestations mainly include macrocytic anemia, recurrent infections, and neurological deficits. The neurological manifestations include progressive psychomotor retardation, behavioral disorders, and early-onset seizures.. From early infancy, a Chinese boy had experienced macrocytic anemia, leukopenia, thrombocytopenia, recurrent pneumonia, diarrhea, and mouth ulcers. He also presented with progressive neurological symptoms.. A novel mutation in the SLC46A1 gene was identified, and HFM was diagnosed at 18 months of age.. After the HFM diagnosis, the boy was treated with folinic acid.. Folinic acid supplementation is effective and may offer life-changing therapy for patients with HFM.

Topics: Asian People; China; Folic Acid Deficiency; Humans; Infant; Leucovorin; Malabsorption Syndromes; Male; Mutation; Proton-Coupled Folate Transporter; Vitamin B Complex

The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.

Topics: Animals; Cells, Cultured; DNA Breaks, Double-Stranded; Embryonic Stem Cells; Fetus; Folic Acid Antagonists; Folic Acid Deficiency; G1 Phase; Gene Expression Regulation, Developmental; Genes, rRNA; Histones; Leucovorin; Methotrexate; Mice; Neural Tube Defects; Pol1 Transcription Initiation Complex Proteins; Transcription, Genetic

Folinic acid-responsive seizures (FARS) are a rare treatable cause of neonatal epilepsy. They have characteristic peaks on CSF monoamine metabolite analysis, and have mutations in the ALDH7A1 gene, characteristically found in pyridoxine-dependent epilepsy. There are case reports of patients presenting with seizures at a later age, and with folate deficiency due to different mechanisms with variable response to folinic acid supplementation. Here, we report 2 siblings who presented with global developmental delay and intractable seizures who responded clinically to folinic acid therapy. Their work-up included metabolic and genetic testing. The DNA sequencing was carried out for the ALDH7A1 gene, and the folate receptor 1 (FOLR1) gene. They had very low 5-methyltetrahydrofolate (5-MTHF) in CSF with no systemic folate deficiency and no characteristic peaks on neurotransmitter metabolite chromatogram. A novel mutation in the FOLR1 gene was found. The mutation in this gene is shown to affect CSF folate transport leading to cerebral folate deficiency. The response to treatment with folinic acid was dramatic with improvement in social interaction, mobility, and complete seizure control. We should consider the possibility of this treatable condition in appropriate clinical circumstances early, as diagnosis with favorable outcome depends on the specialized tests.

Topics: Atrophy; Brain; Brain Diseases, Metabolic, Inborn; Child Development Disorders, Pervasive; Child, Preschool; Consanguinity; Developmental Disabilities; Early Diagnosis; Electroencephalography; Epilepsies, Myoclonic; Female; Folate Receptor 1; Folic Acid Deficiency; Humans; Leucovorin; Magnetic Resonance Imaging; Male; Mutation, Missense; Point Mutation; Pyridoxine; Siblings; Tetrahydrofolates

Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.. We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.. Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.. The follow-up periods ranged from one to eight years. Cases 1-4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.. No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients. Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.. Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.. Eudrac T2007-00-6748-23.

Topics: Adolescent; Adult; Brain; Child; Dietary Supplements; Female; Folic Acid Deficiency; Follow-Up Studies; Humans; Kearns-Sayre Syndrome; Leucovorin; Magnetic Resonance Imaging; Male; Vitamin B Complex; Young Adult

Dihydrofolate reductase (DHFR) is a critical enzyme in folate metabolism and an important target of antineoplastic, antimicrobial, and antiinflammatory drugs. We describe three individuals from two families with a recessive inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency due to a germline missense mutation in DHFR, resulting in profound enzyme deficiency. We show that cerebral folate levels, anemia, and pancytopenia of DHFR deficiency can be corrected by treatment with folinic acid. The characterization of this disorder provides evidence for the link between DHFR and metabolism of cerebral tetrahydrobiopterin, which is required for the formation of dopamine, serotonin, and norepinephrine and for the hydroxylation of aromatic amino acids. Moreover, this relationship provides insight into the role of folates in neurological conditions, including depression, Alzheimer disease, and Parkinson disease.

Topics: Amino Acid Metabolism, Inborn Errors; Amino Acid Sequence; Anemia, Megaloblastic; Base Sequence; Biopterins; Brain; Female; Folic Acid; Folic Acid Deficiency; Humans; Infant; Leucovorin; Magnetic Resonance Imaging; Male; Models, Molecular; Molecular Sequence Data; Pancytopenia; Pedigree; Protein Conformation; Sequence Homology, Amino Acid; Tetrahydrofolate Dehydrogenase

Cerebral folate deficiency presents during infancy with irritability, deceleration of head growth, seizures, and progressive cognitive and motor impairment. Although low serum folate levels have been found in patients with schizophrenia, we describe the first case of cerebral folate deficiency presenting as catatonic schizophrenia. A 13-year-old previously healthy boy presented to our hospital with a 17-month history of schizophrenic symptoms with progressively worsening catatonia. On admission, he demonstrated near-complete mutism, frequent enuresis and encopresis, and severe psychomotor retardation. Our initial diagnostic evaluations, including brain magnetic resonance imaging, electroencephalogram, and routine metabolic tests, were normal. A lumbar puncture done to look for neurotransmitter defects or cerebral folate deficiency revealed low levels of 5-methyltetrahydrofolate (31 nmol/L; reference range, 40-150 nmol/L). He also had elevated titers of folate receptor-blocking antibodies. He was treated for the next 9 months with 5-formyltetrahydrofolate (folinic acid), but his catatonia was unchanged.

Topics: Adolescent; Diagnosis, Differential; Folic Acid Deficiency; Humans; Leucovorin; Male; Schizophrenia, Catatonic; Treatment Outcome

Topics: Antiparkinson Agents; Atrophy; Basal Ganglia; Brain Diseases, Metabolic; Carbidopa; Cerebellum; Demyelinating Diseases; Dystonia; Female; Folic Acid Deficiency; Humans; Leucovorin; Levodopa; Male; Syndrome; Tetrahydrofolates; Treatment Outcome; Vitamin B Complex

Folate is a B vitamin, deficiency of which appears to increase the risk of developing several malignancies including colorectal cancer. In contrast to the cancer-promoting effect of folate deficiency in normal tissues, several lines of evidence indicate that folate depletion suppresses the progression of existing neoplasms and enhance the sensitivity of cancer cells to chemotherapy. Folate mediates the transfer of one-carbon necessary for the de novo biosynthesis of purines and thymidylate, and hence is an essential factor for DNA synthesis and repair, and the maintenance of DNA integrity and stability. Folate deficiency induces DNA strand breaks, increases uracil misincorporation into DNA, impairs DNA repair and appears to induce apoptosis. Although the effects of folate depletion on DNA integrity and apoptosis and on subsequent cancer development, progression and treatment in colonic epithelial cells have been well characterized, it is largely unknown at present how folate depletion modulates specific upstream genes in apoptosis and cancer pathways that regulate these processes. We therefore investigated the effects of folate depletion on expression of genes involved in apoptosis and cancer pathways in four human colon adenocarcinoma cell lines in an in vitro model of folate deficiency. Apoptosis and cancer pathway-specific mini-microarray were used to screen for differentially expressed genes in response to folate deficiency, and the expression of seven most notably and consistently affected genes was confirmed by real time RT-PCR. Our data suggest that folate deficiency affects the expression of key genes that are related to cell cycle control, DNA repair, apoptosis and angiogenesis in a cell-specific manner. Cell-specificity in gene expression changes in response to folate deficiency is likely due to significant differences in molecular and phenotypic characteristics, growth rates and intracellular folate concentrations among the four cell lines.

Topics: Adenocarcinoma; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Deoxyuridine; DNA; Folic Acid Deficiency; Gene Expression Regulation, Neoplastic; Humans; Leucovorin; Models, Biological; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction

Topics: Administration, Oral; Anemia, Megaloblastic; Anemia, Pernicious; Antibodies; Folic Acid; Folic Acid Deficiency; Humans; Injections, Intramuscular; Intrinsic Factor; Leucovorin; Schilling Test; Vitamin B 12; Vitamin B Complex

Cerebral folate deficiency is characterized by low cerebrospinal fluid (CSF) concentrations of 5-methyltetrahydrofolate and a broad spectrum of clinical signs and symptoms. A patient with progressive spasticity, gait disturbance, speech difficulties, initially diagnosed as a recessive spastic paraplegia recovered on folinic acid (15-30 mg/day) and her 5-methyltetrahydrofolate in CSF normalized. This report demonstrates the importance of CSF investigation in the diagnosis of cerebral folate deficiency and efficiency of folinic acid (5-formyltetrahydrofolate) supplementation.

Topics: Brain Diseases; Child; Child, Preschool; Dietary Supplements; Dose-Response Relationship, Drug; Female; Folic Acid Deficiency; Gait; Humans; Leucovorin; Life Style; Movement Disorders; Paraplegia; Pregnancy; Speech Disorders; Tetrahydrofolates

The authors describe a 6-year-old girl with developmental delay, psychomotor regression, seizures, mental retardation, and autistic features associated with low CSF levels of 5-methyltetrahydrofolate, the biologically active form of folates in CSF and blood. Folate and B12 levels were normal in peripheral tissues, suggesting cerebral folate deficiency. Treatment with folinic acid corrected CSF abnormalities and improved motor skills.

Topics: Adaptation, Physiological; Autistic Disorder; Cerebral Cortex; Child; Developmental Disabilities; Disease Progression; Female; Folic Acid; Folic Acid Deficiency; Genetic Predisposition to Disease; Humans; Intellectual Disability; Leucovorin; Mutation; Recovery of Function; Reduced Folate Carrier Protein; Seizures; Tetrahydrofolates; Transcription Factors; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Dietary Supplements; Drug Antagonism; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate; Purines

Topics: Adolescent; Adult; Biomarkers; Blood-Brain Barrier; Brain; Cerebrospinal Fluid; Child; Child, Preschool; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Predictive Value of Tests; Reference Values; Rett Syndrome; Tetrahydrofolates; Treatment Outcome

Topics: Adult; Antidepressive Agents; Depressive Disorder; Drug Resistance; Drug Therapy, Combination; Female; Folic Acid Deficiency; Humans; Leucovorin

Topics: Anencephaly; Diet; Dietary Supplements; Disease Outbreaks; Female; Folic Acid Deficiency; Humans; Infant, Newborn; Leucovorin; Pregnancy; Pregnancy Complications; Spinal Dysraphism

The biochemical basis for modulation of fluorouracil (FU) activity by leucovorin is elevation of the metabolite methylenetetrahydrofolate, which stabilizes the inhibitory ternary complex formed between thymidylate synthase and the active metabolite of FU, 5-fluorodeoxyuridylate. Folic acid, because it can also potentially be metabolized to methylenetetrahydrofolate, was evaluated for its ability to potentiate FU antitumor activity in a dietary folic acid restricted murine model. The plasma pharmacokinetics and tissue distribution of folic acid and all stable metabolites thereof were determined in the model to establish administration schedules. FU was administered to mice implanted subcutaneously with a mammary adenocarcinoma 4 hr after folic acid administration, when the metabolites, methylenetetrahydrofolate and tetrahydrofolate, were elevated maximally in both plasma and tumor tissue. While FU alone suppressed growth 25%, folic acid in combination with FU increased growth suppression to over 70%. These results indicate that folic acid is a potent modulator of FU activity and could be considered as an alternative to leucovorin in the clinical setting.

Topics: Animals; Antidotes; Antimetabolites, Antineoplastic; Diet; Disease Models, Animal; Drug Synergism; Fluorouracil; Folic Acid; Folic Acid Deficiency; Leucovorin; Mice; Mice, Inbred C3H; Neoplasms, Experimental

A dietary folic acid depleted mouse model was established and used to evaluate the relationship between elevation of reduced folates after leucovorin (LV) administration and potentiation of fluorouracil (FU) response of an implanted tumor. C3H mouse mammary adenocarcinomas from mice maintained on a folic acid deplete diet had modestly decreased methylenetetrahydrofolate and tetrahydrofolate levels, and were somewhat less responsive to FU alone compared with replete animals. LV administration resulted in a substantial increase in tumor folate by 1 hr that returned to near basal levels by 12 hr. Reduced folates were elevated to a lesser extent in animals on a standard diet. Tumor growth was suppressed approximately 80% when FU was administered to depleted animals 1 hr after LV administration, compared with approximately 50% suppression in control mice. LV administered 12 hr before FU resulted in tumor growth stimulation that was consistent with the pronounced growth stimulation when LV was administered without FU. These results show that dietary folic acid depletion can lead to a more responsive FU/LV model and that administration of LV at an improper time before FU not only can fail to potentiate but also can result in tumor growth stimulation.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Diet; Drug Synergism; Fluorouracil; Folic Acid Deficiency; Leucovorin; Mammary Neoplasms, Experimental; Mice

A comprehensive pharmacokinetic study of leucovorin (5-formyltetrahydrofolate, 5-HCO-FH4) and its metabolites was conducted in plasma, liver and implanted tumor tissue from mice maintained on a low folic acid diet. While it has been previously demonstrated that the antitumor activity of fluorouracil (FU) can be potentiated by 5-HCO-FH4, the optimum time for administration of FU after 5-HCO-FH4, to maximally elevate the active folate metabolite methylenetetrahydrofolate in tumor has not been established. Human plasma studies have defined the pharmacokinetics of circulating 5-HCO-FH4 and its metabolites, but comparison with human tumor accumulation has not been practicable because of sampling difficulties. As an alternative, a mouse model system, based on low dietary folic acid, was used to evaluate plasma, liver and implanted tumor reduced folates after administration of 5-HCO-FH4.. Plasma and tissue samples were collected from folate-deplete mice over a 12-h period after intraperitoneal administration of 90 mg/kg [R, S] 5-HCO-FH4. Reduced folates were evaluated using a ternary complex assay.. The time at which maximal accumulation of parent compound and all metabolites, except 5-methyltetrahydrofolate (5-CH3FH4), occurred in tumor was the same as in plasma. Alternatively, peak liver accumulation was delayed relative to plasma for all folates except 5-CH3FH4.. The results suggest that mouse plasma accumulation of reduced folates, with the exception of 5-CH3FH4, can predict tumor accumulation. Hence, evaluation of human plasma folate accumulation may potentially provide a means to improve the timing of the administration of FU relative to 5-HCO-FH4 to achieve a superior therapeutic outcome.

Topics: Animals; Carbon-Nitrogen Ligases; Drug Synergism; Folic Acid; Folic Acid Deficiency; Leucovorin; Ligases; Liver; Mice; Mice, Inbred C3H; Neoplasms, Experimental

Topics: Adolescent; Female; Folic Acid Deficiency; Humans; Injections, Intramuscular; Leucovorin; Malabsorption Syndromes; Time Factors

Topics: Adult; Anesthesia, Obstetrical; Cesarean Section; Female; Folic Acid Deficiency; Humans; Leucovorin; Pancytopenia; Pregnancy; Pregnancy Complications, Hematologic

The authors report a case of a patient who in the 24th week of a twin pregnancy became sero-positive for toxoplasmosis. This was diagnosed by cordocentesis as being infected, and the treatment was therefore started with pyrimethamine and sulfadiazine and folic acid at the 28th week of pregnancy. At 35 weeks, the patient had an acute medullary aplasia due to the absence of the folates. The mother's state was improved rapidly by giving her folinic acid and the twins were normal haematologically. In this case, the authors point out how important the folates are in a pregnancy, especially in twin pregnancies, and point out the precautions that have to be taken when treatment with pyrimethamine and sulfadiazine is started for congenital toxoplasmosis.

Topics: Adult; Anemia, Aplastic; Anemia, Sideroblastic; Cordocentesis; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Trimester, Second; Pregnancy, Multiple; Pyrimethamine; Spiramycin; Sulfadiazine; Toxoplasmosis; Twins

An AIDS patient with cerebral toxoplasmosis had a folate deficiency-induced acute pancytopenia, which was rapidly reversed by the administration of folic acid. This observation is particularly important as a possible preventive therapy to be given to all HIV-infected patients because of the anti-folic activity of the majority of anti-infectious agents used during the course of this disease and the many potential sites of hematopoietic involvement. The patient's condition is stressed because the undernourished subject is at greater risk for this type of manifestation.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; Brain Diseases; Folic Acid Antagonists; Folic Acid Deficiency; HIV-1; Humans; Leucovorin; Male; Pancytopenia; Pyrimethamine; Toxoplasmosis

In order to evaluate the efficacy of oral administration of a pharmacological dose of folic or of folinic acid to prevent the folate deficiency in patients with inflammatory bowel disease (IBD) treated with salicylazosulfapyridine (SASP) (1g twice daily at meal times), two groups of 15 patients with IBD received 15 mg/day of folic or folinic acid for one month. In both the groups there were ten patients affected by Crohn's disease and five patients affected by ulcerative colitis. Before starting the treatment, the plasma folate and the red blood cell (RBC) folate concentrations did not statistically differ between the two groups. After one month the mean increase in RBC folate concentration was significantly greater after folinic therapy then after folic acid therapy (910 +/- 383 versus 570 +/- 212 ng/ml; p less than 0.01), while no difference was observed in the mean increase of plasma folate level (19.8 +/- 6.6 versus 18.5 +/- 5.0 ng/ml). It was concluded that: a) both folic and folinic acid could restore and enlarge the body stores of folate in patients with IBD treated with SASP, when administered at the dose of 15 mg daily for one month; b) folinic acid seems to be more efficient in enlarging the body stores of the vitamin than folic acid.

Topics: Administration, Oral; Adolescent; Adult; Colitis; Female; Folic Acid; Folic Acid Deficiency; Humans; Ileitis; Ileum; Leucovorin; Male; Middle Aged; Sulfasalazine

Because phytohaemagglutinin-stimulated lymphocytes acquire folate deficiency in vitro, we have re-examined the claim that the deoxyuridine suppression test (dU-test) based on such cells helps to diagnose megaloblastic states. dU-test results were obtained from the phytohaemagglutinin-stimulated blood cells of 77 patients at 6 concentrations of dU. 21 megaloblastic patients with cobalamin or folate deficiency did not have a mean blood dU-test result significantly higher than that of 21 normoblastic patients at any concentration of dU. Among all patients, however, there was a weak correlation between the blood and marrow dU-test results. Folic acid corrected the blood dU-test results more in the normoblastic than the megaloblastic patients, and a difference between the two groups appeared, but a large overlap persisted. Blood dU-test results tend to be higher in megaloblastic patients, but acquired folate deficiency obscures the distinction from normoblastic patients so that the test is not of diagnostic value.

Topics: Aged; Blood Cells; Deoxyuridine; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Osmolar Concentration; Phytohemagglutinins; Vitamin B 12 Deficiency

Agranulocytosis and aplastic anaemia associated with sulphasalazine are well recognised, but pancytopenia caused by acute megaloblastic arrest of haemopoiesis while taking sulphasalazine has not previously been described. We report three patients who, after taking sulphasalazine for over two years, suddenly developed severe pancytopenia with gross megaloblastic changes in the marrow. In two patients there was a good response to high dose oral folic acid but the third required folinic acid. The mechanism appears to be acute folate deficiency, and the requirement for folinic acid in one case suggests that the known inhibition of folate metabolism by sulphasalazine also contributes. The syndrome appears to be associated with high dosage and slow acetylator status. The drug has been successfully restarted at reduced dosage with folate supplements in two patients both of whom were slow acetylators. In the third case, whose acetylator status is not known, progression of her disease led to colectomy.

Topics: Adolescent; Adult; Bone Marrow; Female; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Male; Pancytopenia; Sulfasalazine

Topics: Animals; Folic Acid Deficiency; Gingiva; Leucovorin; Male; Methotrexate; Periodontium; Rats; Rats, Inbred Strains

Biochemical investigations show a decreased bioavailability of 5-methyl-tetrahydrofolic acid in vitamin B12 deficient human cell cultures and bone marrow cells. Tetrahydrofolic acid cannot be liberated from its storage form. This so-called methyl-folate-trap results in a functional folic acid deficiency which is the pathogenetic principle of the defect in the cell proliferation in patients with vitamin B12 deficiency. This knowledge of biochemical mechanisms leads to the identification of rare disorders in the metabolism of vitamin B12 and folic acid. After methotrexate treatment a rescue effect with its antidote Leucovorin can only be achieved, if the ratio antidote: methotrexate is at least 10:1. This ratio is important in cell cultures as well as in bone marrow cells in vivo. The results lead to a formula for the calculation of the optimal dosis to reach a secure rescue for individual patients after high-dose methotrexate treatment. This makes the high-dose methotrexate regimen a treatment modality for malignant tumors without any side effects.

Topics: DNA; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Methotrexate; Neoplasms; Vitamin B 12; Vitamin B 12 Deficiency

The role of vitamin B12 in the folate dependent biosynthesis of thymidine nucleotides is controversial. In an attempt to clarify this, three methods have been used to assess the relative efficacy of vitamin B12 (hydroxocobalamin) and various folate analogues in titrated concentrations at correcting 'de novo' thymidylate synthesis by megaloblastic human marrow cells: (1) The deoxyuridine (dU) suppression test which analyses the reduction in (3H)-thymidine labeling of DNA by unlabeled dU. Marrow cells were also labeled with (6-3H)-dU with assessment of (2) its incorporation into DNA and (3) the accumulation of (6-3H)-deoxyuridine monophosphate (3H-dUMP). The three methods gave similar results. In both, N6-formyl tetrahydrofolate (formyl-FH4) was the most effective agent at correcting thymidylate synthesis in megaloblastic anemia due to vitamin B12 or folate deficiency. Vitamin B12 corrected the lesion in vitamin B12 deficiency but not in folate deficiency. Tetrahydrofolate (FH4) and folic acid were effective in deficiency of vitamin B12 or folate, although in both deficiencies they were less effective than formyl-FH4. Methyl-FH4 was effective in folate deficiency but not in vitamin B12 deficiency. These results confirm the failure of methyl-FH4 utilisation in vitamin B12 deficiency. They suggest that if vitamin B12 is needed in the formylation of FH4, this is a minor role in provision of the correct coenzyme for thymidylate synthesis compared with its major role of provision of FH4 from methyl-FH4.

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Bone Marrow; Deoxyuridine; DNA; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Tetrahydrofolates; Thymine Nucleotides; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Anemia, Macrocytic; Anemia, Megaloblastic; Female; Folic Acid; Folic Acid Deficiency; Humans; Infant; Injections, Intramuscular; Intestinal Absorption; Leucovorin; Malabsorption Syndromes; Probenecid

Granulocytes from a boy with congenital transcobalamin II (TC II) deficiency were found to have abnormally low antibacterial activity against Staphylococcus aureus. Transfusion of normal plasma supplemented with hydroxocobalamin temporarily restored granulocyte bactericidal activity to normal. Granulocyte function was also temporarily restored by oral leucovorin. The defect appears to be causally related to the patient's TC II deficiency and indirectly to an intracellular deficiency of cobalamin and folate coenzymes [1].

Topics: Blood Bactericidal Activity; Blood Proteins; Blood Transfusion; Child; Folic Acid Deficiency; Granulocytes; Humans; Leucovorin; Male; Staphylococcus aureus; Transcobalamins

Topics: Folic Acid Deficiency; Humans; Leucovorin; Tablets

Topics: Bacteria; Bacterial Infections; Drug Combinations; Drug Resistance, Microbial; Drug Synergism; Folic Acid; Folic Acid Deficiency; Humans; Leucovorin; Sulfamethoxazole; Trimethoprim

Topics: Animals; Brain; Carbon Radioisotopes; Folic Acid; Folic Acid Deficiency; Injections, Intraperitoneal; Intestinal Mucosa; Kidney; Leucovorin; Liver; Methotrexate; Rats; Skin; Tritium

Topics: Adult; Anemia, Sideroblastic; Erythropoiesis; Folic Acid Deficiency; Hemochromatosis; Humans; Leucovorin; Male

Topics: Administration, Oral; Anemia, Macrocytic; Child; Consanguinity; Female; Folic Acid; Folic Acid Deficiency; Humans; Injections, Intramuscular; Intestinal Absorption; Leucovorin; Metabolism, Inborn Errors; Recurrence; Stomatitis; Vitamin B 12; Yeast, Dried

Topics: Anemia, Macrocytic; Animals; Binding Sites; Biological Assay; Folic Acid; Folic Acid Deficiency; Humans; Lacticaseibacillus casei; Leucovorin; Methods; Milk; Protein Binding; Proteins; Radiometry; Spectrophotometry; Temperature; Tetrahydrofolates; Tritium

Topics: Aged; Biological Assay; Folic Acid; Folic Acid Deficiency; Gastrectomy; Glutamates; Humans; Intestinal Absorption; Intestine, Small; Jejunum; Leucovorin; Male; Peptides; Time Factors

Topics: Adult; Anemia, Hemolytic; DNA; Fanconi Syndrome; Female; FIGLU Test; Folic Acid Antagonists; Folic Acid Deficiency; Glutathione Reductase; Hemoglobinuria, Paroxysmal; Histidine; Humans; Leucovorin; Male; Thalassemia; Vitamin B 12 Deficiency; Waldenstrom Macroglobulinemia

Topics: Adult; Anemia, Macrocytic; Female; Folic Acid; Folic Acid Deficiency; Hemorrhagic Disorders; Humans; Leucovorin; Obstetric Labor, Premature; Pregnancy; Pregnancy Complications, Hematologic; Thrombocytopenia

Topics: Animals; Antimalarials; Blood; Bone Marrow; Bone Marrow Cells; Folic Acid; Folic Acid Deficiency; In Vitro Techniques; Intestines; Leucovorin; Male; Rats

Topics: Anemia; Anemia, Macrocytic; Blood; Bone Marrow Examination; Deficiency Diseases; Diarrhea; Diarrhea, Infantile; Folic Acid; Folic Acid Deficiency; Humans; Infant; Infant Nutrition Disorders; Infections; Israel; Leucovorin

Topics: 4-Aminobenzoic Acid; Aminopterin; Animals; Chloroquine; Folic Acid; Folic Acid Deficiency; Leucovorin; Malaria; Mice; Pharmacology; Plasmodium berghei; Pyrimethamine; Research

Topics: Alcoholic Beverages; Alcoholism; Alkaline Phosphatase; Anemia; Anemia, Macrocytic; Aspartate Aminotransferases; Bilirubin; Blood Chemical Analysis; Blood Proteins; Bone Marrow Examination; Ethanol; Folic Acid; Folic Acid Deficiency; Hematopoiesis; Humans; Iron; Leucovorin; Liver Function Tests; Pharmacology; Reticulocytes; Toxicology

Topics: Anemia; Anemia, Macrocytic; Anemia, Megaloblastic; Ascorbic Acid; Asian People; Blood Chemical Analysis; Bone Marrow Examination; Dietary Carbohydrates; Dietary Proteins; Folic Acid; Folic Acid Deficiency; Leucovorin; Lipids; Myanmar; Vitamin B 12

Topics: Alcohol Oxidoreductases; Aminopterin; Folic Acid; Folic Acid Deficiency; Leucovorin; Liver; Mitochondria; Oxidoreductases

Topics: Acute Disease; Antimetabolites; Folic Acid; Folic Acid Deficiency; Leucovorin; Leukemia; Leukemia, Myeloid

Topics: Animals; Folic Acid; Folic Acid Deficiency; Leucovorin; Rats

Topics: Chlortetracycline; Folic Acid; Folic Acid Deficiency; Leucovorin