Cerebral folate deficiency and CNS inflammatory markers in Alpers disease

Hasselmann, Oswald; Blau, Nenad; Ramaekers, Vincent; Quadros, Edward V.; Sequeira, Jeffrey M.; Weissert, M

doi:10.1016/j.ymgme.2009.08.005

Cited by 72 publications

(60 citation statements)

References 21 publications

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“…Treatment with oral folinic acid (leucovorine) resulted in improvement of CSF folate level and seizure frequency, and communicative abilities improved [124]. Therefore, CSF folate may be deficient in disorders that lead to mtDNA depletion.…”

Section: Cofactor Use In Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically and clinically heterogeneous group of autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. MDS are due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial nucleotide synthesis (TK2, SUCLA2,

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Section: Cofactor Use In Mdsmentioning

confidence: 99%

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

2013

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“…This suggests that other factors, which may be genetic, epigenetic, or environmental, are important in modulating the pathogenesis of POLG mutations. Autoantibodies have been detected in the blood and CSF of children with POLG mutations [26,27]. Furthermore, one patient with compound heterozygous known pathogenic POLG mutations had neuropathological features of acute disseminated encephalomyelitis (ADEM) [27].…”

Section: Immune Mechanisms and Mitochondrial Epilepsymentioning

confidence: 99%

“…Epilepsy has been reported in association with cerebral folate deficiency (CFD) in Kearns-Sayre syndrome (KSS) and AlpersHuttenlocher syndrome [26,31]. Patients with KSS appear to be particularly susceptible to developing CFD, possibly because the choroid plexus is disrupted in this condition [32].…”

Section: Cerebral Folate Deficiencymentioning

confidence: 99%

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

Rahman

2015

Epilepsy & Behavior

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“…In the latter patients CSF folates are undetectable, thus much lower than in other forms. Further monogenic causes of CFD include 5,10-methylene-tetrahydrofolate reductase (MTHFR) deficiency [16], 3-phosphoglycerate dehydrogenase (PGDH) deficiency dihydropteridine reductase (DHPR) deficiency [17], as well as with Rett syndrome [18], Aicardi-Goutières syndrome [19], Alpers disease [20], Kearns-Sayre syndrome [21] and hereditary folate malabsorption [22]. Unfortunately, in a minority of patients suffering from CFD the etiology could not be identified.…”

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confidence: 99%

Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport

Opladen

Blau

Ramaekers³

2010

Molecular Genetics and Metabolism

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a b s t r a c tMetabolic breakdown of valproate (VPA), carbamazepine (CBZ) and phenytoin (PHT) by the cytochrome P450 pathway generates toxic drug intermediates and reactive oxygen species (ROS). This mechanism has been suspected to play a role in the pathogenesis of secondary cerebral folate deficiency (CFD). Using KB-cell cultures, highly expressing the folate receptor 1 (FOLR1), the effect of antiepileptic drugs (AEDs) and reactive oxygen species (ROS) on the FOLR1 dependent 5-methyltetrahydrofolate (MTHF) uptake was studied. MTHF uptake is time and concentration dependent and shows saturation kinetics. At physiological MTHF concentrations the high-affinity FOLR1 represents the predominant mechanism for cellular incorporation, while at high MTHF concentrations other transport mechanisms participate in folate uptake. Exposure to PHT for more than 8 h led to a higher MTHF uptake and decreased cell count, whereas MTHF uptake remained unaltered by VPA and CBZ. However, exposure to superoxide and hydrogen peroxide radicals significantly decreased cellular MTHF uptake. By specific elimination and downregulation of FOLR1 using phosphatidyl-inositol-specific phospholipase C (PIPLC) and siRNA silencing, it was shown that ROS not only inhibited FOLR1 mediated MTHF uptake but also affected all other mechanisms of membrane-mediated MTHF uptake. Generation of ROS with the use of AED might therefore provide an additional explanation for the disturbed folate transfer across the blood-CSF barrier in patients with CFD.Ó 2010 Elsevier Inc. All rights reserved.Introduction 5-Methyltetrahydrofolate (MTHF) is the predominant form of folate in plasma and cerebrospinal fluid (CSF). MTHF and its other reduced folates are involved in various one-carbon exchange reactions like the de novo synthesis of purines and thymidylate. MTHF is also co-factor of methionine synthase catalyzing the conversion of homocysteine to methionine and is the precursor for the activated methyl-group donor S-adenosyl-methionine which acts as an important co-factor used in more than 100 different methyltransfer reactions including methylation of DNA, proteins and phospholipids [1].Folates are required by all cell types. Folate transport across cell membranes is facilitated by at least three different mechanisms: folate receptors (FOLR1 and FOLR2) with high affinity for MTHF, the reduced folate carrier (RFC) having low affinity for MTHF and, by passive MTHF diffusion at extremely high extracellular concentrations [2]. The glycosyl phosphatidyl-inositol (GPI) membrane-anchored folate receptors (FOLR1 and FOLR2) posses high affinity for folate at concentrations within the nanomolar range and is therefore able to bind physiological levels of folate [3,4]. FOLR1 shows a higher affinity for MTHF compared to FOLR2. The FOLR proteins are crucial for the assimilation, distribution and retention of food folates while intestinal absorption depends also on intact function of the co-transporter called the proton-coupled folate transporter (PCFT) [5,6]. FOLR proteins have ...

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Cerebral folate deficiency and CNS inflammatory markers in Alpers disease

Cited by 72 publications

References 21 publications

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

Mitochondrial DNA Depletion Syndromes: Review and Updates of Genetic Basis, Manifestations, and Therapeutic Options

Pathophysiology of mitochondrial disease causing epilepsy and status epilepticus

Effect of antiepileptic drugs and reactive oxygen species on folate receptor 1 (FOLR1)-dependent 5-methyltetrahydrofolate transport

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