Hereditary Folate Malabsorption
2002; Wolters Kluwer; Volume: 81; Issue: 1 Linguagem: Inglês
10.1097/00005792-200201000-00004
ISSN1536-5964
AutoresJames I. Geller, David Kronn, Somasundaram Jayabose, Claudio Sandoval,
Tópico(s)Metabolism and Genetic Disorders
ResumoIntroduction The coenzyme forms of folic acid function in the metabolism of single-carbon groups involved in the biosynthesis of pyrimidines, purines, serine, and methionine (38,50,57,129). Folate deficiency can result from nutritional deficiency, malabsorption (celiac disease, inflammatory bowel disease, alcoholism, etc), medications, and diseases involving increased cell turnover (hemolytic anemia, psoriasis). Moreover, inborn errors of metabolism affecting folate transport and metabolism have been described. Wellsubstantiated disorders include methylene tetrahydrofolate reductase deficiency (MIM 2362501), functional methyl tetrahydrofolate:homocysteine methyl transferase deficiency caused by mutations in the gene for methionine synthase reductase (MIM 236270) or mutations in the gene for methionine synthase itself (MIM 250940), glutamate formiminotransferase deficiency (MIM 229100), and hereditary folate malabsorption (MIM 229050)—a folate transport disorder (94) (Figure 1). The clinical features of these metabolic conditions are diverse, and treatment is aimed to correct the enzymatic disturbance.Fig. 1: Processes and reactions affected by inherited disorders of folate metabolism. 1. Methylene-H4Folate reductase deficiency;2. and 3. Functional methionine synthase deficiency (cbIE, methionine synthase reductase deficiency; cbIG, methionine synthase deficiency);4. Glutamate formiminotransferase deficiency;5. Hereditary folate malabsorption. Disorders involving folate transport are indicated by a broken line, whereas those involved in folate metabolism are indicated by a solid line. The numbered steps show the sites of well-characterized inherited disorders of folate transport or metabolism. H2Folate = dihydrofolate; H4Folate = tetrahydrofolate; methyl-B12 = methylcobalamin; GAR = 5-phosphoribosylglycinamide; FGAR = α-N-Formyl-glycinamide ribonucleotide; AICAR = 5-phosphoribosyl-5-aminoimidazole-4-carboxamide; C2+ C8 = carbons 2 and 8 of purine ring. Adapted from reference 94, Rosenblatt DS, Fenton WA. Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Valle D, Sly WS, Childs B, Kinzler KW, Vogelstein B, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, ©2001. Reproduced with permission of The McGraw-Hill Companies.Hereditary folate malabsorption (HFM) is a rare genetic disorder first described by Lubhy et al in 1961 (66–68). They described 2 sisters who suffered from megaloblastic anemia, ataxia, mental retardation, and seizures. Both demonstrated defective absorption of folate across the gastrointestinal tract and defective transport of folate across the central nervous system (CNS) blood brain barrier. Lanzkowsky et al (60) later confirmed these findings in their description of a second affected family. HFM usually presents in the first few months of life with recurrent or chronic diarrhea, failure to thrive, megaloblastic anemia, oral ulcers, and progressive neurologic deterioration. Laboratory findings of HFM are low serum and erythrocyte folate levels, low cerebral spinal fluid (CSF) folate levels, and abnormally high urinary formiminoglutamic acid (FIGLU) excretion (2). Methionine may be low in the serum and CSF, and other abnormalities in serum amino acids may be found (published in this report). Characteristically, hematologic manifestations are reversible with relatively low levels of folate, and folate uptake into cultured cells is preserved (129). The normal CSF:serum folate ratio of 3:1 is not achieved despite correction of serum levels during replacement therapy (81,114). Due to the rarity of HFM no treatment consensus exists. Neurologic outcome in HFM is dismal, unless the condition is diagnosed early and treated aggressively. Seventeen cases (10 index patients and their 7 affected sibs) have been reported in the literature. The precise underlying defect has not been determined; however, it is most likely inherited in an autosomal recessive fashion based on affected sibs of both genders and consanguineous matings (25,60–61,66–69,80–81,100,108,114–115,120). Additionally, during the last decade, new discoveries have occurred with respect to folate absorption and transport, folate carriers, and folate receptors. Noteworthy, the "reduced folate carrier" has been identified and localized to chromosome 21 (75), and its link to folate absorption in the human small intestine has been well described (23,76,99). This report serves several purposes. A new family with HFM is presented documenting, in conjunction with previously reported cases, that HFM (and severe folate deficiency) can present as a clinically significant immunodeficient state. Oral replacement therapy, previously unsuccessful in adequately preventing neurologic disease in HFM, is proven feasible in our cases of HFM. All published cases and relevant literature pertaining to HFM are reviewed to characterize this disorder better so that early diagnosis can be achieved more readily for future patients. The potential genetic basis for HFM is reviewed, as is the pathophysiology of immunologic and neurologic disease in HFM. The current understanding of folate absorption and transport, and aspects of the folate deficient state, that is, the neurologic and immunologic consequences of folate deficiency, are reviewed and summarized in course. Methods The MEDLINE (National Library of Medicine, Bethesda, MD) database was used via numerous search phrases including, but not limited to, hereditary folate malabsorption, congenital folate malabsorption, folate absorption, folate malabsorption, folate and immune, folate and neuro, folate receptors, reduced folate carrier. All relevant texts and case reports of the 10 index patients were thoroughly reviewed. Relevant laboratory data of each index case, as well as experimental data, were analyzed. Theories addressed by such investigators are discussed. The diagnosis of HFM was made, in each case, by the individual authors—no strict definition has been made. The current family report is included in this review. Family Report Case 1 A 6.5-month-old Puerto Rican girl was referred to our hospital with a history of recurrent diarrhea, gastroesophageal reflux, frequent upper respiratory infections, bilateral pneumonia, urinary tract infection, eosinophilia, anemia, anorexia, poor weight gain, and oral ulcers. She weighed 3.4 kg when born at 38 weeks' gestation via cesarean section, secondary to fetal distress, to a 32-year-old gravida-8 (4 live births, 3 alive and 1 dead; 2 spontaneous abortions; and 2 elective abortions) woman. The parents are nonconsanguineous. The family history revealed that the patient's sister had also experienced recurrent diarrhea, pulmonary disease, eosinophilia, and seizures. The sister developed the adult respiratory distress syndrome and died from sepsis at the age of 4 months. An evaluation for folate malabsorption was not performed. At the age of 1 month, the patient had an upper respiratory infection, which recurred every 3 to 4 weeks. Diarrhea began at the age of 2 months, with poor response to multiple nutritional adjustments. Pallor was noted at that time. Mucositis was evident by 3 months of age. At 3.5 months an upper gastrointestinal series confirmed reflux, at which time ranitidine (Zantac) and cisapride (Propulsid) therapy was initiated. At 4.5 months, fever was noted in association with increasing watery stools. After unsuccessful outpatient management, the patient was hospitalized. During the 5-week hospitalization, the patient suffered from bilateral pneumonia of unknown etiology as well as infection of the stool and urinary tract with Pseudomonas aeruginosa. Despite adequate management of these infections, diarrhea and poor feeding persisted. During this period, thrombocytopenia and anemia were noted. Two packed red blood cell transfusions were given. The patient was transferred to our institution on cimetidine (Tagamet), cisapride (Propulsid), carnitine (Carnitor), multivitamins (MVI) and "hematametics" (iron and folic acid [1 mg/day]). She appeared slightly irritable with a strong cry. Admission weight was 6.27 kg (10%), height was 61 cm (3%), and head circumference was 41 cm (5%). She was alert and responsive. Her general physical examination was normal and no dysmorphic features were evident. Neurologic examination showed severe head lag and generalized hypotonia. Extraocular movements were intact, without any notable facial asymmetry or tongue deviation. A gag response was elicited. Tone and muscle bulk were diminished. Deep tendon reflexes were found to be 3/5 in all 4 extremities, and plantar responses were up-going bilaterally. She could not sit and did not lean forward on her hands. She did not push to stand when held erect. She reportedly was able to reach for objects, but would not pass objects from hand to hand. She verbalized vowel sounds (by report only). After our initial evaluation the child was discharged in stable condition. Results of laboratory evaluations performed are summarized in Table 1.TABLE 1: Laboratory investigationsDue to increasing diarrhea, anorexia, and dehydration, the patient was readmitted at the age of 7 months. The admission weight was 5.46 kg (<5%). Throughout the hospitalization, anorexia and diarrhea waxed and waned. Nasogastric tube feeding was initiated for caloric support. Stools that had been intermittently guaiac positive became grossly bloody. One unit of packed red blood cells was transfused. The diagnosis of tyrosinemia type I (MIM 276700) was considered due to the clinical course and the finding of succinylacetone on urine organic acid analysis. NTBC (2-(2-nitro-4-trifluoro-methylbenzolyl)-1,3-cyclo-hexanedione) was instituted after emergent institutional review board approval and written informed consent for the presumed treatment of tyrosinemia type I, along with a low phenylalanine/tyrosine diet, without response, until enzyme studies confirmed that tyrosinemia was not present. The diarrhea continued and upper endoscopy revealed mild chronic inflammation of the esophagus and duodenum, as well as antral stromal edema and mild chronic inflammation. Oral ulcers became evident. Colonoscopy revealed a large rectal ulcer. Packed red blood cell transfusions and platelet transfusions were given as necessary. Bone marrow examination revealed a normoblastic marrow. The patient suffered recurrent respiratory distress requiring tracheal intubation. Bronchoalveolar lavage, performed at the age of 8.25 months, recovered Pneumocystis carinii, which responded to treatment. At the age of 8 months, serum folic acid levels were evaluated and found to be 0.4 μg/L (normal: 5–15 μg/L). Folic acid was started at 1 mg orally every day. CSF folate levels were obtained and found to be 0.1 μg/L (normal: 11–48 μg/L). The clinical and laboratory findings were consistent with HFM. We titrated the level of oral folinic acid to 150 mg daily based on serum and CSF folate levels. CSF folate levels were always found to be lower than serum levels drawn concurrently (Table 2). Magnetic resonant imaging (MRI) of the brain showed no evidence of intracranial calcifications or demyelination. Electromyographic (EMG) studies showed no evidence of myopathic or neuropathic changes. On high-dose folinic acid, weight gain was rapid and laboratory values normalized.TABLE 2: Folate: Serum and CSF levels related to supplemental dose (Case 1)The patient is now 48 months old and is receiving folinic acid 400 mg daily. Since diagnosis and initial treatment of P. carinii pneumonia (PCP), she has remained free of major infections. Developmentally, she has reached all age-appropriate milestones. Her neurologic exam is normal. Currently she is only receiving speech therapy. Case 2 The 2-month-old sister of Case 1 was evaluated for HFM because of the family history. At the time of evaluation she had an upper respiratory tract infection and had begun to lose weight. She weighed 3.6 kg when born at 38 weeks' gestation via cesarean section. The physical examination was essentially normal. The serum and CSF folate were both 20 μg/L and the CSF folate was 11 μg/L. At 12 months of age she is thriving without any evidence of neurodevelopmental delay. Discussion Overview of folate metabolic pathways Folate coenzymes are the central participants in single-carbon transfer reactions. 5,10-methylene tetrahydrofolate is used unchanged for the synthesis of thymidylate, reduced to 5-methyl tetrahydrofolate for the synthesis of methionine, or oxidized to 10-formyl tetrahydrofolate for the synthesis of purines. During histidine catabolism, a formimino group is transferred to tetrahydrofolate followed by release of ammonia and generation of 5,10-methenyl tetrahydrofolate. Figure 2 shows folate and its congeners.Fig. 2: Folic acid and congeners.Epidemiology and genetics of HFM HFM has been reported to affect children of multiethnic groups (25,81,100,120). As with other rare autosomal recessive traits, consanguinity has been reported in almost half of reported HFM affected families. (60–61,100,115,120) In addition, 40% of cases reported, including ours, have demonstrated a death in a sib before the index case report (25,80–81,120) (Table 3). Of the 7 presumably affected sibs referred to in the case reports there were 3 girls, 1 boy, and 3 gender unknown. The cause of death was uncertain in all but 1 sib (pallor, lethargy, and diarrhea).TABLE 3: Characteristics of HFM index patients, previous and present reportsExplanation is lacking for several observed features of HFM. Most of the affected children are girls. Two of the fathers (of affected children) that were tested showed an intermediate absorption pattern for folate and slightly low serum folate levels (81,100). In our family report both parents had normal serum and red blood cell folate levels. The individual cases of HFM demonstrate varied abilities to absorb pharmacologic doses of folate. Urbach et al (120) described a patient with "presumed" HFM who had normal CSF:serum folate ratios. Taking these observations together suggests that HFM is an autosomal recessive disorder with different mutations in a single gene or genetic heterogeneity. Malatack et al (69) proposed the possibility that 2 different genes may need to be defective for HFM to be expressed by an individual based on the phenotype observed in their patient. Diagnosis of HFM History and physical: Evaluation of a child for suspected HFM should include a history focusing on evidence of gastrointestinal, neurologic, immunologic, or hematopoietic system dysfunction. Chronic or recurrent diarrhea, mucosal ulceration, poor feeding, and anorexia are often noted. Loss of developmental milestones or frank failure to thrive, seizures, or peripheral neuropathy have also been described in children with HFM. Hematopoietic dysfunction may present as recurrent or atypical infections, anemia, and/or easy bruising. A complete developmental evaluation must be performed. Family history should be reviewed for evidence of consanguinity, unexplained infant death, and any dysfunction of the above-mentioned systems in relatives of the index case. Physical examination is particularly important in detecting any neurologic deficits, assessing growth parameters, and for noting any skin findings that may represent an underlying bone marrow or T-cell disturbance. HFM and folate levels: Children with clinical signs and symptoms and a medical history consistent with HFM should undergo concurrent measurements of their serum and CSF folate levels. Diagnostic criteria for the diagnosis of HFM are not yet defined; however, the simultaneous defect in the transport of folate across the gastrointestinal tract and the blood brain barrier is pathognomonic and paramount for identifying the disorder. In each of the cases described to date, defective folate transport across the gastrointestinal tract was demonstrated, and the majority of authors demonstrated subnormal CSF folate transport, as evidenced by the inability to achieve the normal 3:1 CSF:serum folate ratio in their patients (see Table 3). The CSF:serum ratio was established in 103 patients (32 normal subjects, 33 with folate deficiency, and 38 with pernicious anemia) (3). This ratio was demonstrated in each patient and across patient groups. The demonstration of an abnormal CSF:serum folate ratio in the presence of severe folate deficiency is probably all that is required for making the diagnosis of HFM. Assays measuring levels of folate in the serum and in erythrocytes remain useful methods for diagnosing folate deficiency. Erythrocyte folate status is thought to be superior because it is not affected by recent dietary fluctuations in folate content or by drugs, but it is influenced by vitamin B12 status (134). Folate deficiency and amino acid abnormalities in HFM: Metabolic profiling (plasma amino acid analysis) is useful for detecting folate deficiency. Utilization of these assays has led to detection of tissue vitamin deficiency in certain clinical situations where vitamin assays have yielded normal results and peripheral blood samples lacked evidence of macrocytosis, anemia, or hypersegmented neutrophils that would otherwise indicate folate deficiency. Also, normalization of abnormal findings found on these tests, once folate replacement has been initiated, confirms the diagnosis of folate deficiency (134). Plasma amino acid analyses have revealed increased levels of serum cystathionine, serum N,Ndimethylglycine, and serum N-methylglycine (sarcosine) in states of folate deficiency (2,112,134). Stabler et al (112) showed that sarcosine, in particular, was abnormally elevated in 60% of patients with folate deficiency, but not in patients with cobalamin deficiency. The highest sarcosine level reported in their study of 25 patients with folate deficiency was 43.2 mmol/L (normally undetected). Betaine therapy, given to a subset of patients studied, led to slightly higher levels of sarcosine (up to 49.3 mmol/L). Numerous reports exist of individuals and families with "hypersarcosinemia" associated with folate deficiency (not caused by sarcosine dehydrogenase deficiency) (11,51,117). Such reports document normalization of sarcosine levels coincident with folate replacement therapy. Plasma amino acids from our Case 1 revealed abnormally high sarcosine levels, which continued to increase up to a maximum of 182.9 mmol/L. The escalation of sarcosine levels abruptly ceased, with a return to normal, once adequate folate replacement was initiated. Chemically, 5-methyl-tetrahydrofolate, decreased in states of folate deficiency, normally binds to glycine N-methyltransferase and inhibits its function. During states of folate deficiency, this inhibition is impaired, leading to increased activity of glycine N-methyltransferase and hence, increased production of the end product of the reaction catalyzed by this enzyme, N-methylglycine (sarcosine). Sarcosine dehydrogenase, the enzyme responsible for sarcosine catabolism, requires tetrahydrofolate as a cofactor, and thus displays decreased function in states of folate deficiency. Thus, increased production and decreased catabolism both contribute to hypersarcosinemia in folate deficiency, and the finding of sarcosine in the serum may therefore be useful in the diagnosis of folate deficiency. This finding is specific for folate deficiency; that is, sarcosine levels have not been shown to be associated with vitamin B12 deficiency (2). The reactions described above are part of a complex set of reactions involving the conversion of betaine to glycine which starts with betaine-dependent methylation (an alternative method for converting homocysteine to methionine) and ends with the eventual production of glycine (the breakdown product of sarcosine). Glycine is further cleaved to carbon dioxide and ammonia via a reaction requiring tetrahydrofolate. Steinschneider et al (114) remarked that their patient with HFM had a CSF glycine level, initially elevated, that returned to normal once folate replacement was initiated, and this return of glycine to normal represented improved tetrahydrofolaterequiring glycine cleavage reaction within the CNS. Our investigations also demonstrated increased initial CSF glycine levels and normalization after folate replacement. To our knowledge, increased CSF glycine levels have not been reported previously as a reliable indicator of folate deficiency. The correlation found between CSF glycine levels in patients with HFM and folate deficiency justifies further investigation into the metabolic environment of the CNS and the pathophysiology of neurologic disease resulting from folate deficiency. The finding of an elevated succinylacetone in Case 1 was of concern since it suggested a diagnosis of hepatorenal tyrosinemia (MIM 276700). The patient was started on NTBC because of her critical condition. Therapy with NTBC was discontinued because of thrombocytopenia, and repeat analysis of urine organic acids did not reveal succinylacetone. Absorption and transport of folates Overview of folate absorption: Gastrointestinal absorption of folate begins with conversion of dietary polyglutamate forms into monoglutamate forms via the enzyme hydrolase (folylpolyglutamate conjugase or gamma-L-glutamyl peptidase) (21,45,125). Such hydrolysis occurs either in the gut lumen or on the brush border or inside enterocyte lysosomes (21,125); however, hydrolysis is currently thought to be a prerequisite for significant absorption into the enterocyte (45). Uptake of folate in the gastrointestinal tract predominantly occurs in the proximal small intestine, notably the duodenum and jejunum, via specific transport mechanisms (9–10,32,59,71,98,101,104,133). The majority of folate uptake proceeds in the small intestine via carrier-mediated uptake of predominantly reduced folates, and this system has the ability to uptake folate against a concentration gradient. Intracellular processes include binding, reduction, and methylation (93). Monoglutamates are then transported into the portal venous circulation (18), mostly as reduced folates. Under normal conditions, folate will appear within the portal venous circulation within 15 minutes of ingestion, and reach a peak serum level approximately 1 hour post-ingestion (129). Other contributing factors affecting folate absorption include the enterohepatic circulation of folate (113) and folic acid binding proteins (48,105,123,126). Folate transport: The 2 predominant folate transporters/carriers involved in cellular uptake of folate found in humans are the reduced folate carrier (RFC) and the folate receptor (FR) systems. The RFC is considered to have a high affinity for reduced folates, whereas FRs have been shown to have a higher affinity for oxidized folates. In general, the RFC is considered a low-affinity, high-capacity system; whereas FRs are considered high-affinity, low-capacity systems. The 2 systems are thought to coexist on many cells working independently of each other (5–6). The reduced folate carrier: The RFC was identified and mapped to chromosome 21 (75). Said et al (99) documented the functional expression of the mRNA complementary to RFC1 in the human small intestine by Northern blot analysis. The term human intestinal folate carrier-1 (hIFC-1) was instituted. Nguyen et al (76) reported the distribution of hIFC-1: RFC mRNA expression to preferentially distribute in the human jejunum epithelial cells, especially in the upper half of the villi by in situ hybridization. In order of distribution, this protein is found in the human placenta, small intestine, colon, thymus, prostate, testis, ovaries, spleen, peripheral leukocytes, heart, brain, liver, skeletal muscle, pancreas, kidney, and lung by Northern blot analysis. Chiao et al (23) demonstrated that RFC-expression regulates pHdependent folate absorption driven by a transmembrane hydrogen ion gradient in mouse small intestine. The pH-dependent mechanism identified was developmentally regulated showing much higher maximum capacity for 5-methyltetrahydrofolate influx in mature absorptive rather than proliferating crypt cells, and an increased RFC-1 gene expression was noted in association with its operation. Its function is saturable. They identified a 58kDa protein on the luminal surface of the enterocyte that occurred with increased mRNA expression of the RFC that appeared to be identical to the protein encoded by RFC mRNA. The RFC resembles the mammalian glucose transporter, a member of the 12 transmembrane domain-spanning membrane transporter family. This protein was also shown to be associated with active transport, preferentially expressed on mature absorptive enterocytes. An alternative carrier was identified as a non-pH-dependent carrier with variable saturability thought to mediate basolateral membrane transport. Folate receptors: FRs have not been isolated in the human small intestine, but their presence on the human colonic mucosa has been characterized, and theories have implicated defective FR function in the pathophysiology of HFM (6). FRs are high-affinity folate binding proteins found within the membranes of cells as 3 isoforms: alpha (trophoblast, KB Cells) (55,84,86), beta (maternal decidua, hematopoietic progenitor cells) (84,107), and gamma (hematopoietic cells) (107). All show significant genetic homology for one another as well as for other folic acid binding proteins. The FRs are glycosyl-phosphatidylinositol anchored with the exception of FR-gamma (a secretory form predominantly expressed in hematopoietic cells) (6). Various mechanisms are hypothesized to explain how FRs transport folate across membranes including hydrogen pumps (83), endocytosis (62), and potocytosis (4). The potocytic mechanism is currently believed to be the likely mode of transport. The knockout murine model of folate binding protein 1 (the mouse homologue of the human FR alpha) is an embryonic lethal, and offspring can only be rescued with suprapharmacologic doses of folic acid (8,78). FRs are found in the male and female genitourinary tract, submandibular and bronchial glands, alveolar pneumocytes, breast acinar cells, human milk, thyroid, pancreas, and fibroblasts (5). Functions attributed to such receptors include folate transport into hematopoietic progenitor cells as well as certain malignant cells; transport across barrier systems such as the human placenta, renal tubule, and milk; modulation of intracellular metabolism of folate; control of cell proliferation (hematopoietic progenitor cells); and as an antibacterial apparatus (6,26). A high expression of FRs has been found in nasopharyngeal carcinomas, cervical carcinomas, ovarian carcinomas and choriocarcinomas, and lower expression in endometrial carcinomas, breast carcinomas, colorectal carcinomas, renal cell carcinomas, sarcomas, and brain tumors. This has led to intense research into the role of such receptors in the pathophysiology of these cancers. Moreover, FRs may impart sensitivity to "antifolate" chemotherapy, and may be utilized to target chemotherapy. Alternative transport systems in the human intestine: Numerous intestinal transport systems have been described in animal and human studies. Distinct carrier-mediated transport systems have been described on the jejunal enterocyte apical membrane (23), jejunal enterocyte basolateral membrane (23), colonic enterocyte apical membrane (32), and on the enterocyte apical membranes equally represented throughout the human small and large intestine (133). The latter 2 systems may, in fact, represent the same systems. The jejunal enterocyte apical membrane transport system described by Chiao et al (23) is thought to be the dominant folate transporter in the human intestine—the RFC system. The other systems described by Zimmerman et al (133) (referred to by Malatack et al [69] as the pH-independent pathway) and Dudeja (32) appear to represent alternative carrier-mediated apical membrane transport systems that have a lower affinity for folate than the jejunal RFC system and have slightly different operating mechanisms of transport. Colonic representation of the RFC protein is well described (76), but the significance of this finding is unclear. The significance of colonic FR (found at low concentration) is also not clear. However, the role that alternative carrier systems found in the intestine (including colon) play is of great interest, especially as alternative folate absorption systems are thought to be critical in the predisposition, pathophysiology, and treatment of colon cancer (54). In addition, transport of bacterially produced folate in the colon is thought to be important in folate deficiency and in small intestinal disease. Lastly, the documentation of other transport systems for folate explains the feasibility of treating some patients with HFM via the oral route (131), sparing the child daily or weekly injections. Transport of folates into the CNS: Lanzkowsky et al (60–61) noted that despite adequate or high serum folate levels, the normal 3:1 CSF:serum ratio was unattainable in their patient with HFM. The first evidence that the CNS has a system to concentrate folate within the CSF came from the findings of Weckman et al (127) when they established that CSF levels are physiologically 3 times that of serum levels. These data were confirmed by Alperin and Haggard (3), and in addition, the primary CNS folate was identified as 5-methyl-tetrahydrofolate (a reduced form of folate). The CNS lacks dihydrofolate reductase, and therefore is incapable of reducing oxidized folates, highlightin
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