Congenital folate malabsorption

Corbeel, L; Berghe, Greet Van den; Jaeken, Jacques; Tornout, Jan Van; Eeckels, R

doi:10.1007/bf00442302

Cited by 69 publications

(33 citation statements)

References 25 publications

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“…These findings confirm earlier studies indicating that relatively low folate levels are sufficient to correct hematopoietic abnormalities in patients with hereditary folate malabsorption, whereas repeated administration of high doses of folic acid is required to increase folate levels in the cerebrospinal fluid and compensate for impaired folate transport into the brain. 30,34 Direct analysis of the cerebrospinal fluid/serum ratio in PCFT-mutant mice will be required to validate this hypothesis and is currently underway.…”

Section: Discussionmentioning

confidence: 99%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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IntroductionFolate is an essential cosubstrate of many biochemical reactions, such as the de novo synthesis of purines and pyrimidines, methionine, and deoxythymidylate monophosphate. 1,2 Mammals cannot synthesize folate; therefore, inadequate dietary supply or folate malabsorption results in defective DNA synthesis. One of the first manifestations of a folate deficiency is in the rapidly proliferating cells of the hematopoietic system, leading to pancytopenia and anemia of the megaloblastic type. Patients with megaloblastic anemia demonstrate ineffective erythropoiesis by harboring large immature red blood cell (RBC) precursors that fail to survive to the postmitotic, terminal stages, undergoing premature apoptosis. 2 Three mammalian folate transporter systems have been described to date in a variety of tissues: (1) the bidirectional reduced folate carrier 1 (RFC1), also known as SLC19A1, 3,4 (2) the glycosyl-phosphatidylinositol-anchored folate receptors (FOLR1, FOLR2, and FOLR4) and one secreted receptor in humans without a mouse homolog (FOLR3), 5 and (3) the human proton coupled folate transporter (PCFT). 6-8 The RFC1 transporter is expressed ubiquitously, including the brush-border membrane of epithelial cells in the small intestine. 9 Although RFC1 is necessary for folate transport in erythroid cells, its involvement in intestinal folate uptake has not been confirmed. 6 Inactivation of RFC1 in mice by homologous recombination led to either embryonic lethality or defective erythropoiesis in pups born to mothers who were supplemented with 1 mg daily subcutaneous doses of folic acid. 10,11 Because this transporter functions at a neutral pH optimum whereas the majority of intestinal folate transport occurs in an acidic luminal milieu, RFC1 is an unlikely candidate for an intestinal folate transporter. 7 The role of FOLR1 in folate absorption and transport has also been demonstrated, where a 60% to 70% reduction was observed in plasma folate of FOLR1 Ϫ/Ϫ mice fed low folate and normal chow. 12 FOLR1 also regulates folate homeostasis via endocytotic mechanisms during embryonic development, and mice rendered null for this receptor display severe morphogenetic abnormalities and die in utero unless provided supraphysiologic concentrations of either folinic acid or 5-methyltetrahydrofolate. 5,13 The PCFT transporter is highly expressed in tissues involved in folate and heme transport, including the duodenum and liver. 6,14 Initially, PCFT was identified as a low-affinity, pHindependent heme transporter 14 and then later described to function as a low pH-dependent folate transporter in intestinal cells. 6 The latter role of the transporter was confirmed by the identification of loss-of-function mutations in the human PCFT gene in persons diagnosed with hereditary folate malabsorption syndrome. 6 Studies have also indicated that PCFT facilitates folate transport during folate receptor-mediated endocytosis, where FOLR1 binds folate, and its export into the cytosol is driven by PCFT activity as the vesicle undergoes en...

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Section: Discussionmentioning

confidence: 99%

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

Salojin

Cabrera²,

Sun

et al. 2011

Blood

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“…This patient was the subject of a previous case report. 8 Patient P2 was also the subject of a prior case report, 3 and was the ninth child (female) of Turkish parents who denied consanguinity. She presented at 5 months of age with a history of fever, diarrhea, and convulsions.…”

Section: Patientsmentioning

confidence: 99%

“…1,2 If untreated, the disease is fatal and, if treatment is delayed, the neurologic deficits can become permanent. 3,4 Hence, it is important that physicians are aware of this disorder and establish a diagnosis and institute treatment as early as possible in infancy. The clinical characteristics of HFM and its treatment were the subject of a recent comprehensive review.…”

Section: Introductionmentioning

confidence: 99%

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The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption

Zhao¹,

Min²,

Qiu³

et al. 2007

Blood

146

171

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Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by impaired intestinal folate absorption and impaired folate transport into the central nervous system. Recent studies in 1 family revealed that the molecular basis for this disorder is a loss-of-function mutation in the PCFT gene encoding a proton-coupled folate transporter. The current study broadens the understanding of the spectrum of alterations in the PCFT gene associated with HFM in 5 additional patients. There was no racial, ethnic, or sex pattern. A total of 4 different homozygous mutations were detected in 4 patients; 2 heterozygous mutations were identified in the fifth patient. Mutations involved 4 of the 5 exons, all at highly conserved amino acid residues. A total of 4 of the mutated transporters resulted in a complete loss of transport function, primarily due to decreased protein stability and/or defects in membrane trafficking, while 2 of the mutated carriers manifested residual function. Folate transport at low pH was markedly impaired in transformed lymphocytes from 2 patients. These findings further substantiate the role that mutations in PCFT play in the pathogenesis of HFM and will make possible rapid diagnosis and treatment of this disorder in infants, and prenatal diagnosis in families that carry a mutated gene. (Blood. 2007;

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“…It presents in early infancy with megaloblastic anemia, poor growth, diarrhea, infections, stomatitis, hypotonia, and progressive neurological deterioration including severe developmental delay and seizures that could be refractory to treatment (Diop-Bove et al 1993Fernandes et al 2012;Scriver et al 1995;Zhao et al 2012). To date 31 patients have been reported in the literature (Atabay et al 2010;Borzutzky et al 2009;Corbeel et al 1985;Diop-Bove et al 2013;Geller et al 2002;Hansen and Blau 2005;Jebnoun et al 2001;Kishimoto et al 2014;Lanzkowsky et al 1969;Lasry et al 2008;Malatack et al 1999;Ponz et al 1898;Rosenblatt and Fenton 2001;Santiago-Borrero et al 1973;Shin et al 2011;Sofer et al 2007;Steinschneider et al 1990;Su 1976;Urbach et al 1987;Wang et al 2014;Zhao et al 2007). It is imperative that the patients be treated very early and effectively with 5-formyltetrahydrofolate (folinic acid) in order to prevent irreversible neurological disease (Surtees 2001;Urbach et al 1987;Wang et al 2014;Whitehead 2006).…”

Section: Introductionmentioning

confidence: 99%

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

et al. 2015

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Hereditary folate malabsorption is characterized by folate deficiency with impaired folate transport into the central nervous system (CNS). This disease is characterized by megaloblastic anemia of early appearance, combined immunodeficiency, seizures, and cognitive impairment. The anemia and immunologic disease are responsive but neurological signs are refractory to folic-acid treatment. We report a 7-year-old girl who has congenital folate deficiency and SLC46A1 gene mutation who is unable to transport folate from her gut to the circulatory system and consequently from the blood to the cerebrospinal fluid (CSF). As a result she developed undetectable 5-methyltetrahydrofolate levels in her plasma and CSF and became immunocompromised and quite ill. Intramuscular treatment with 5-formyltetrahydrofolate (folinic acid) was therapeutic at her presentation and has been successful preventing other signs and symptoms of hereditary folate malabsorption even at relatively low CSF levels. Although difficult, early detection and diagnosis of cerebral folate deficiency are important because folinic acid at a pharmacologic dose may normalize outcome in PCFT gene defects, as well as bypass autoantibody-blocked folate receptors and enter the cerebrospinal fluid by way of the reduced folate carrier. This route elevates the 5-methyltetrahydrofolate level within the central nervous system and can prevent the neuropsychiatric disorder. CSF levels of 5-methyltetrahydrofolate between 18 and 46 nmol/L may be sufficient to eradicate CNS disease.

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Congenital folate malabsorption

Cited by 69 publications

References 25 publications

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption

CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency

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