Hereditary Folate Malabsorption (2002)

Introduction 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 in neurologic in is in cases of cases and to HFM are to this disorder that early can be achieved for The genetic for HFM is as is the of and neurologic in The of folate absorption and transport, and of the folate that the neurologic and of folate deficiency, are and in The of not hereditary folate folate folate folate folate and folate and folate folate and of the index patients of index as well as by are The of HFM in by the has been The family report is in this A to with a of recurrent diarrhea, urinary tract anemia, and oral to to a and 2 and 2 The are The family that the recurrent diarrhea, disease, and seizures. The the and from the of for folate malabsorption not the of the an to the of 2 with to nutritional that by months of months an gastrointestinal confirmed and therapy in with the the the suffered from of as well as of the and urinary tract with of these and this and blood cell The to on and and folic acid with a and and normal and no features Neurologic severe and or A and found to be in and not and not on not to to for not from to report the in of are in 1: Laboratory to diarrhea, and the the of 7 The the and and for that been of blood cells The of (MIM to the clinical and the of on acid and for the treatment of with a low confirmed that not The and chronic of the and as well as and chronic Oral a blood cell and as a The suffered recurrent the of to the of 8 serum folic acid levels and found to be acid folate levels and found to be The clinical and findings with the of oral acid to based on serum and folate folate levels found to be serum levels of the brain no of or no of or and and levels to is months and is acid and treatment of has of has neurologic is is 2 The of for HFM of the family the of an tract and to The The serum and folate both The and brain The and amino acid and blood are in 1. on oral acid months later the serum folate and the folate months of is of of folate metabolic Folate are the central in single-carbon tetrahydrofolate is for the of to tetrahydrofolate for the of or to tetrahydrofolate for the of a is to tetrahydrofolate by of and of 2 folate and its acid and and of HFM HFM has been reported to of groups with other rare autosomal recessive has been reported in of reported HFM affected of cases have demonstrated a in a the index report the 7 affected sibs to in the and The of in and of HFM index and present is for several features of of the affected are of the affected that an absorption for folate and low serum folate levels family report both normal serum and blood cell folate The cases of HFM to of et al described a with HFM who normal CSF:serum folate these that HFM is an autosomal recessive disorder with mutations in a gene or genetic et al the that 2 may to be defective for HFM to be by an based on the in their of HFM and of a for HFM include a on of or system or recurrent diarrhea, and are of or failure to thrive, or have been described in with may present as recurrent or anemia, A be be for of and of the in of the index is in neurologic and for findings that may an underlying or HFM and folate with clinical and and a with HFM of their serum and folate for the of HFM are not however, the defect in the transport of folate across the gastrointestinal tract and the blood brain is and for the of the cases described to defective folate transport across the gastrointestinal tract and the of demonstrated folate transport, as by the to the normal 3:1 CSF:serum folate ratio in their patients The CSF:serum ratio in patients normal with folate deficiency, and with This ratio demonstrated in and across The of an CSF:serum folate ratio in the of severe folate deficiency is that is for the of levels of folate in the serum and in for folate folate is to be it is not affected by in folate or by it is by Folate deficiency and amino acid abnormalities in amino acid is for folate of these has to of deficiency in clinical have normal and blood of anemia, or that folate of findings found on these folate replacement has been the of folate deficiency amino acid have increased levels of serum serum and serum in of folate deficiency et al that in abnormally in of patients with folate deficiency, not in patients with cobalamin The reported in their of patients with folate deficiency therapy, to a of patients to levels of to of and with with folate deficiency caused by deficiency) of levels with folate replacement amino acids from abnormally high levels, to to a of The of levels with a to folate replacement in of folate deficiency, to and its of folate deficiency, this is to increased of and increased of the of the by this the for tetrahydrofolate as a and function in of folate increased and both to in folate deficiency, and the of in the serum may be in the of folate This is for folate deficiency; that levels have not been to be with deficiency (2). The reactions described are of a of reactions involving the of to with for to and with the of of is to and a et al that their with HFM a that to normal folate replacement and this of to normal the demonstrated increased levels and folate increased levels have not been reported previously as a of folate The found levels in patients with HFM and folate deficiency into the metabolic of the and the of neurologic from folate The of an in of it a of (MIM The on of with of and of acids not and transport of of folate absorption of folate with of forms into forms the or in the or on the or however, is to be a for significant absorption into the of folate in the gastrointestinal tract in the small the and transport The of folate uptake in the small intestine uptake of and this system has the to uptake folate a include and are into the as normal folate the of and a serum (129). affecting folate absorption include the of folate and folic acid Folate The 2 folate involved in uptake of folate found in are the folate and the folate The is to have a high for whereas have been to have a for the is a whereas are The 2 are to on cells of other The folate The identified and to chromosome 21 et al the functional of the to in the human small intestine by The human folate et al reported the of to in the human in the of the by in of this is found in the human small and by et al demonstrated that folate absorption by a in small The identified for in and an increased gene in with its function is They identified a on the of the that occurred with increased of the that to be to the by The the a of the family. This to be with transport, on identified as a with to Folate have not been in the human small their on the human has been and have defective function in the of HFM are folate found the of cells as and show significant genetic for as well as for other folic acid The are with the of in are to transport folate across and The is to be the likely of The of folate of the human is an and can be with of folic acid are found in the and and human and to include folate transport into cells as well as transport across as the human and of metabolism of of cell and as an A high of has been found in and and in cell and brain This has to into the of in the of these Moreover, may to and may be to transport in the human transport have been described in and human transport have been described on the and on the the human small and intestine The 2 in the The transport system described by et al is to be the folate in the human The other described by et al to by et al as the and to transport that have a for folate the system and have of of the is well described the of this is The of low is not the that found in the intestine is of as folate absorption are to be in the and treatment of transport of folate in the is to be in folate deficiency and in small disease. the of other transport for folate the of patients with HFM the oral the or of into the Lanzkowsky et al that despite or high serum folate levels, the normal 3:1 CSF:serum ratio in their with The first that the has a system to folate the from the findings of et al that levels are that of serum confirmed by and and in the folate identified as of The and is of that folate uptake the uptake of and identified the as the of folate uptake in the of and that this system and The of and folic acid that this is in to for folate transport into the et al reported a of an transport defect across the with progressive neurologic by a spinal tract and found to have abnormally low with abnormally low a defect in the the of has been to be its it that the defect in the have been inherited from the the The described by et al a of a and the defect found to be however, the their report with cases of HFM be with This to the of the to folate uptake into the The that their into the that the system in the is to a system to early life folate uptake and system defective in may be that transport of is by a that may with folate transport have been described by et al The has a system for the absorption of that is from other transport that later in of folate across the The by an affected with HFM can transport folate to the is The that the system is present high in the is in this this may an for of folate from to is with HFM have an folate transport defect localized to the gastrointestinal tract and blood brain or a defect in the folate the system is defective in the a of folate deficiency may folate deficiency (and have been to the of it has been that the system not involved in folate across the and the system a and may to be the folate transport The defect underlying absorption on patients with HFM have absorption of A and the found to be the of first A and and and and and normal in the of the of folate absorption across the gastrointestinal tract The absorption of both and forms of folate as well as forms and are affected and of small bowel have normal it has that HFM a defect in gastrointestinal absorption to folic acid and its are a of the underlying of that 2 by folate is for small of folate, and a by of folate are The of to folate, of that not a by folate is that HFM may a defect in a the of both the gastrointestinal tract and the these a report by that absorption is functional the of the gastrointestinal tract and blood brain for the in findings and of patients with HFM the oral et al a the underlying of They that 2 by folate is in and a that folate They that both of folate absorption be affected in with They that folate absorption the is likely to be defective in who show a defect in transport across the are the in to the of the of or the gene defect in the is previously and clinically the transport the is The molecular in HFM is not of the of the in folate mutations are for Moreover, as by et al 2 gene affecting the transport system and the other affecting the be for HFM to be clinically folate on the uptake of in and of that the “reduced folate carrier” is this has been that the is present in significant in the human The defect in HFM is by a defect across the gastrointestinal and by et al and et al to a defect in a present in both transport a to the of involved in significant absorption this as the for folate absorption defective in Additionally, the reported by et al that not an of HFM from The of et al have their reference to to an folate transport that is present on the the small and have a in the of by et al to 2 of index cases show absorption and significant in to oral folate The described by et al of a with defective gastrointestinal transport to the and of the have forms of mutations of the are for in cells and may the in folate disorders as of the the system in the of HFM is and of the folate and their in HFM no mutations of have been reported in patients with a in 2 of has been identified This in with the in the reductase gene may folate and HFM and with HFM as index cases demonstrated a of with et al reported a with HFM who suffered recurrent from the of et al described a with HFM who suffered of the and gastrointestinal and This during second of life from et al described a with HFM who presented with to report a with HFM who suffered recurrent and gastrointestinal tract a urinary tract an of in with a and for several sibs of with as in have to on HFM index and the and cells are of the The of and for is and is by the of that the of the and normal is for the gene in the of for and folate are the of the biosynthesis of and for deficiency of folate result in and cell is to the anemia, and in affected with folate deficiency The of folate deficiency on and has been Both defective purine and have been demonstrated to during of folate deficiency in have that and is affected by folate deficiency increased normal of into is by This is of a of reactions the of to a the folate as a of severe folate deficiency, this is is to be the of the system affected most by folate in the of folate deficiency to a to et al and in and folate replacement They found as well as treatment of the underlying folate the on the with HFM described by et al and et al et al that in patients an increased uptake of and these the with as in They later that not folate deficiency to in abnormalities are found in and and of found to be with of folate The and abnormalities in from defective to be reversible folate findings found by Lanzkowsky et al in their with demonstrated increased and other during the megaloblastic however, no found during the is affected by folate deficiency, as by the in HFM to the by have defective purine biosynthesis from as a of The precise by folate deficiency significant is in a with methionine synthase deficiency who suffered recurrent and early that the methionine deficiency in this in in this for in folate deficiency may be that levels of for the of the of by both and cells with an of function and in folate deficiency have et al reported defective of by in their with A with deficiency described with a to or to a underlying both deficiency et al report the of and folic acid on function in patients with deficiency and with folic acid of to in and acid deficiency not found to significant et al reported in of 2 patients They that is affected by folate and deficiency, deficiency to by et al defective in patients normal patients with folate deficiency demonstrated this however, both patients that may have to a defect from folate to function in with folate deficiency include small groups of The report by et al that a is to the folate deficiency and HFM and patients with HFM have has been reported in treated with the et al that folate replacement may have the in their and folate replacement therapy during the of They that folate replacement to a or the folate itself for the to findings of with and of from folate replacement The of folate replacement and of in is suffered recurrent the that in the of by a of folate replacement folate the with and in the of the folate by and not on with this during this from the in a fashion with the human are to their are and the first for in the with folate deficiency itself is the of the The of for those with HFM is by the these have on the severe folate deficiency, be of the of with early during replacement HFM and neurologic to and severe progressive neurologic is an outcome of HFM and as by et al is the therapy is with HFM can present with a of neurologic and to and mental retardation, are the most neurologic of described in of findings are Methionine treatment for Folate is for methionine and methionine may be low in of severe folate Methionine found to be low in the normal in the to reactions and to be the methyl in in the of and low in serum as this has as to the of the of or for of or other is with HFM suffered folate replacement during folate as in this is in with several of increased in patients with folate deficiency folic acid replacement is acid has been described as a folate replacement to the from of patients with patients with deficiency, folate, neurologic by methionine into to cell to a in reactions to methionine Additionally, folate can the for and result in levels with have been found in the and that folate deficiency to is the of the found in HFM with the findings of reported in other have been reported in treatment in of cases, in the and the in with reductase deficiency and other in with the of disease, and folate deficiency and in with folate deficiency with Both patients with HFM who suffered severe to mental retardation, and to this is however, it is to patients with HFM for the of with HFM has been described with of the with and has been described with of and a with a in with a an and Both of the patients described with of their and neurologic folate replacement of with folate deficiency have been of and folic acid replacement in with folic acid deficiency are reported of as well as and to be caused by folate deficiency, have been to folate replacement has been reported and Folate deficiency has been to of the spinal and central to folate deficiency is as well as and have been described in with folate to folate in with low that folate treatment folate deficiency has been to in a of high folic acid levels have been to and folate replacement The folic and disorders has been in the The underlying neurologic and from folate deficiency is as a of methionine and deficiency from folate deficiency, or methyl folate from deficiency, are by as the underlying the neurologic in these during in disorders of metabolism for include of and of for an The of of and to the in in have been that has been to be to of gene and of in the as to from deficiency and a of this is et al as to the of HFM and neurologic in that low methionine for reactions and as and with inborn errors of levels of Additionally, low levels of have been found in the of with of the spinal to folate deficiency neurologic and and in with metabolic involving folate and cobalamin The folate and methionine that is present during severe deficiency be in reactions and to and in the and the of and of the nervous cell as a result of and a significant in the of neurologic of HFM acid has a of oral is in the and to in the The of acid is and may be with and of and have been reported for oral of and oral acid an the serum of and to the The treatment of HFM has the disorder described in The of treatment folate replacement however, treatment be for the of folate as this defective gastrointestinal the defect in folate low folate levels are for and patients with HFM may normal serum folate levels to the of folate for into the the defective transport the for neurologic is the folate achieved in the serum folate levels achieved in the oral therapy are as in cases, as by of reported cases, of serum and folate levels is for and during The folate that is is not and not patients be for folate levels, are during of of acid be for it the blood brain into the Methionine replacement has been for other inborn errors of folate reductase deficiency and glutamate formiminotransferase a for and the for the of to methionine that not folic acid or have been in reductase deficiency with (129). The of these in HFM with a of the of folate these be in and is that folate to be in with HFM who are to or who are and in those who are The and of the folate the and no with HFM has been to be the correct of HFM during include of and folate The of in with HFM for can be are a in the of HFM and the of is are found to be methionine or folate no therapy is however, may be in to and have been to folate absorption treated the oral transport, and metabolism. the folate in the has been to a this system is or of the is in the oral absorption of in is not and have been to folate absorption its on to of folate levels is despite the of that may folate be to folate transport or metabolism. disorders as hereditary folate malabsorption (HFM) as to human to a deficiency in its in this folate The defect in central nervous system transport in HFM with a clinical of the human brain of folate during and are for neurologic The clinical of as the and neurologic clinical of folate deficiency present from the with HFM have that folate is not the gastrointestinal tract into the blood that and can result from folate deficiency, and that folate deficiency can to a clinically significant The of HFM on transport of folate across the gastrointestinal tract and across the blood brain in the clinical amino acid may be in folate deficiency, and in to the molecular underlying folate deficiency is for and treatment for patients with has for uptake to transport folate into cells and across may sites of the human and the of the of and from in the transport, and mutations of folate and folate has with an of in this The of the folate may to the of the genetic underlying and are to this to with HFM is early and of folate neurologic outcome is in cases of HFM by with folate replacement therapy of Moreover, oral acid can be in patients that and are to for the and to for