orders & is T D h e n i r a a p r y B Spector, Brain Disord Ther 2014, 3:2 ISSN: 2168-975X Brain Disorders & Therapy DOI: 10.4172/2168-975X.1000120 Review Article Open Access Vitamin Transport Diseases of Brain: Focus on Folates, Thiamine and Riboflavin Reynold Spector* Department of Medicine, Robert Wood Johnson Medical School, 105 Stone Hill Road, Colts Neck, NJ 07722, USA *Corresponding author: Reynold Spector, Adjunct Professor of Medicine, Department of Medicine, Robert Wood Johnson Medical School, 105 Stone Hill Road, Colts Neck, NJ 07722, USA, Tel: 732-780-5762; E-mail: [email protected] Received date: Apr 2, 2014, Accepted date: Apr 24, 2014, Published date: Apr 30, 2014 Copyright: © 2014 Spector R. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Background: In the last decade, childhood neurological disorders involving inadequate transport of thiamine, riboflavin or folates into brain have been defined. These involve two transporters of folate (the folate receptor α or the proton-coupled folate transporter), one of thiamine and two of the six riboflavin transporters. Depending on the mutations involved, without a specific diagnosis and treatment, the phenotypes vary from mild to severe and fatal. Methods: The purpose of this review is to summarize the relevant physiology and molecular biology before describing the clinical (neurological) manifestations of these either homozygous or compound heterozygous autosomal recessive disorders. In all cases (but one due to easily measurable antibodies to the folate receptor α transporter), the diagnosis can be apodictically confirmed by DNA sequencing of the appropriate genes. Results: With a definitive diagnosis, appropriate ultra-high dose vitamin therapy can be instituted, and, if done before irreversible damage has occurred, can ameliorate or cure the patient. However, treatment is sometimes only marginally successful, in part, because of irreversible brain damage, but also because current oral therapy may not deliver enough of the appropriate vitamin to brain. Approaches to further improve therapy are discussed. Conclusions: In summary, a group of previously undefined childhood vitamin transport neurological disorders have been identified, understood and can be diagnosed on a molecular level. Moreover, this has led to rational and in some cases effective treatment, a triumph of modern pediatric neurology. Keywords: Autosomal Recessive; Vitamins; Mutations; Vitamin (T), there are separate specific transport (homeostatic) systems at the Transporters; Blood-Brain Barrier. BBB and/or BCSFB that help maintain constancy of these vitamins in brain and CSF [1,5-7]. These transport systems do this, in part, Introduction because the plasma vitamin concentration is ~ equal to the half- saturation concentration of these carrier-mediated transport systems Almost one hundred years ago, medical scientists recognized that [1,5-7]. So when the blood level is low, relatively more vitamin is several devastating brain disorders were due to lack of micronutrients transported into brain; when high, relatively less. Moreover, there are e.g., Wernicke’s encephalopathy. Inclusion of certain foods or later also separate specific saturable transport systems in brain cells specific vitamins prevented or cured these disorders if irreversible including neurons that accumulate folates, R and T from the CSF and brain damage had not occurred. But exactly how, and why these extracellular space (ECS) of brain [1-7]. These cellular transport nutrients and vitamins “worked” has only been understood gradually systems are also ~ ½ saturated at the normal CSF/ECS concentration over the last fifty years. One critical point was how do vitamins enter [1-7]. Thus, the brain barrier transport and, in series, the cellular CSF and brain from blood and what are the kinetics [1]. This question transport systems (on the other side of the BBB and BCSFB), provide arose with the discovery of the blood-brain barrier (BBB), consisting impressive control of entry of the transported vitamer (the moiety of of the tight junctions connecting the cerebral capillaries and the blood- the vitamin transported) into brain cells. Moreover, within the brain CSF barrier (BCSFB), the choroid plexus (CP) epithelial cells (which cells there are mechanisms that regulate the amount of vitamin in the secrete the CSF) and the multi-layered arachnoid membrane – both cell. It should be noted that vitamin homeostasis in brain is not due to joined by tight junctions between the cells [1]. With this anatomical lack of turnover. In fact, in brain, T and R turn over relatively rapidly; understanding came the realization that water-soluble molecules the folates very substantially slower [3-7]. However, when these dynamic size of vitamins could not simply diffuse through the BBB and BCSFB transport/homeostatic systems fail, e.g., due to genetic defects, the but there must be specific transport mechanisms [1]. Moreover, there brain becomes deprived of that vitamin. For example, in rabbits which was ~ 4 times more methyltetrahydrofolate (MeTHF) and ascorbic turn out to be a reasonable model for humans, less than 5% of total acid (AA) in CSF than plasma [1-4]. (MeTHF is the principal plasma brain T, R and folate enter brain by simple diffusion [4-7]. and CSF folate.) This suggested there were active transport systems at work [2-5]. Finally, when studied, investigators found that the brain Gradually, over the last decades, with careful physiological, was generally the last organ to be depleted of vitamins in severe pharmacological and biochemical studies in animals and humans, and deficiency states [1,5]. We now know the reason: For the three more recently the use of molecular biological techniques such as vitamins discussed in this paper, folates, riboflavin (R) and thiamine cloning and knock-outs (KO) in mice and rats, it was proven, first in rodents and later in humans, on a molecular level that there were Brain Disord Ther Volume 3 • Issue 2 • 1000120 ISSN:2168-975X BDT, an open access journal Citation: Spector R (2014) Vitamin Transport Diseases of Brain: Focus on Folates, Thiamine and Riboflavin. Brain Disord Ther 3: 120. doi: 10.4172/2168-975X.1000120 Page 2 of 6 indeed multiple separate specific vitamin transport systems at the BBB deoxyuridine via S-adenosylmethionine [13]. Within cells reduced and/or BCSFB for individual vitamins with one exception as folates are polyglutamated; however, only the monoglutamated forms documented below. (There is one system that transports biotin, are transported across cell membranes [1]. pantothenic and lipoic acids at the BBB) [1]. As these systems were In both humans and rabbits, folates, after hydrolysis of described and understood, careful clinical research documented there polyglutamates to monoglutamate forms, are absorbed in the were patients with heretofore unrecognized neurological disorders gastrointestinal tract by a mechanism that depends on the proton- involving these CNS transport systems, some of which were coupled folate transporter (PCFT; SLC46A1) [14]. This transporter is devastating or even fatal. Once understood, in some cases, methods of on the apical (luminal) surface of intestinal epithelia [14]. Exactly how diagnosing and treating these disorders became available. folates exit the intestinal epithelia into the blood remains uncertain, The purpose of this review is to focus on the autosomal recessive possibly by the reduced folate carrier (RFC; SLC 19A1) on the CNS diseases of folate, thiamine and riboflavin transport into brain abluminal side [14]. Once transferred into blood, the concentration of because there is new information on diagnosis and treatment. In each MeTHF (~ 20 nM) is normally maintained relatively constant by case, after a brief background, I will describe the biology of the saturable mechanisms in the both the gastrointestinal tract and kidney transporters, the associated clinical syndromes, and the methods of [5,14]. From the blood, MeTHF enters the CSF by a complex system in diagnosis and treatment. Because in a short review it is not possible to CP involving the folate receptor α (FRα), PCFT and RFC. There is be comprehensive, I will refer to the most recent work – focusing on substantial evidence that FRα binds plasma MeTHF on the blood side the last several years. (basal surface) of the CP and enters endosomes [3,4,14]. MeTHF is then released from the FRα within endosomes by PCFT and exits the To aid in explanatory power, I will first focus on what used to be CP epithelial cells into CSF probably by RFC [14,15]. This complex termed “genetic penetrance” which can now be understood on a system in CP is half-saturated at ~ 20 nM and thus at low plasma molecular basis. In the autosomal recessive transport disorders concentrations pumps more MeTHF into CSF and at high plasma described below (with one exception) for folates, R and T, there are concentrations less, thus providing a crucial part of the homeostatic mutations in each chromosomal transport gene, sometimes the same, system for folates in CSF [5,15]. From CSF, folates gradually enter sometimes different (i.e., homozygous or compound heterozygotes.) brain cells presumably by RFC on cellular surfaces. There appears to In fact, there are examples of deletions, frame shifts, nonsense or be no FRα at the BBB and no or