Hereditary Folate Malabsorption: A Rare Treatable Disorder with Hematological and Neurological Manifestations.
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ABSTRACT:
SUBMITTER: Kumar M
PROVIDER: S-EPMC9996535 | biostudies-literature | 2022 Nov-Dec
REPOSITORIES: biostudies-literature
Publications
Hereditary Folate Malabsorption: A Rare Treatable Disorder with Hematological and Neurological Manifestations.
Kumar Madhan M Yoganathan Sangeetha S Todari Siddarth S Suresh Parvathy P Chandran Mahalakshmi M Danda Sumita S Mathew Leni Grace LG Koshy Beena B Thomas Maya M
Annals of Indian Academy of Neurology 20221101 6
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Project description:RationaleHereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system. Its manifestations mainly include macrocytic anemia, recurrent infections, and neurological deficits. The neurological manifestations include progressive psychomotor retardation, behavioral disorders, and early-onset seizures.Patient concernsFrom early infancy, a Chinese boy had experienced macrocytic anemia, leukopenia, thrombocytopenia, recurrent pneumonia, diarrhea, and mouth ulcers. He also presented with progressive neurological symptoms.DiagnosisA novel mutation in the SLC46A1 gene was identified, and HFM was diagnosed at 18 months of age.InterventionsAfter the HFM diagnosis, the boy was treated with folinic acid.LessonsFolinic acid supplementation is effective and may offer life-changing therapy for patients with HFM.
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Project description:Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder characterized by systemic and central nervous system folate deficiency. Turkish siblings are reported with the clinical syndrome of HFM, homozygous for deletion of 2 bases (c.204_205 delCC) within the first exon of the proton-coupled folate transporter (PCFT) gene, causing a frameshift. Low blood and cerebrospinal fluid folate levels were detected at ages 3.5 and 1 month. Treatment with parenteral 5-formyltetrahydrofolate resulted in normal development now at ages 3 and 1 year. Extending current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum will provide opportunities to define possible genotype-phenotype correlations and clarify the basis for the phenotypic variability that is characteristic of this disorder.
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Project description:Hereditary folate malabsorption (HFM) is an autosomal recessive disorder characterized by impaired intestinal folate absorption and impaired folate transport across the choroid plexus due to loss of function of the proton-coupled folate transporter (PCFT-SLC46A1). We report a novel mutation, causing HFM, affecting a residue located in the 11th transmembrane helix within the external gate. The mutant N411K-PCFT was stable, trafficked to the cell membrane, and had sufficient residual activity to characterize the transport defect and the structural requirements at this site for gate function. The influx Vmax of the N411K mutant was markedly decreased, as was the affinity for most, but not all, folate/antifolate substrates. The greatest loss of activity was for 5-methyltetrahydrofolate. Substitutions with positive charged residues resulted in a loss of activity (arginine > lysine > histidine). Function was retained for the negative charged aspartate, but not the larger glutamate substitutions, whereas the bulky hydrophobic (leucine), or polar (glutamine) substitutions, were tolerated. Homology models of PCFT, in the inward and outward open conformations, based upon the mammalian Glut5 fructose transporter structures, localize Asn411 protruding into the aqueous pathway. This is most prominent when the carrier is in the inward open conformation when the external gate is closed. Mutations at this site likely result in highly specific steric and electrostatic interactions between the Asn411-substituted, and other, residues in the gate region that impede carrier function. The substrate specificity of the N411K mutant may be due to alterations of substrate flows through the external gate, downstream allosteric alterations in the folate-binding pocket, or both.
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Project description:The proton-coupled folate transporter (PCFT; SLC46A1) mediates folate transport into enterocytes in the proximal small intestine; pcft loss-of-function mutations are the basis for hereditary folate malabsorption. The current study explored the roles of Asp residues in PCFT function. A novel, homozygous, loss-of-function mutation, D156Y, was identified in a child of Pakistani origin with hereditary folate malabsorption. Of the 6 other conserved Asp residues, only one, D109, is shown to be required for function. D156Y, along with a variety of other substitutions at this site (Trp, Phe, Val, Asn, or Lys), lacked function due to instability of the PCFT protein. Substantial function was preserved with Glu, Gly, and, to a lesser extent, with Ser, Thr, and Ala substitutions. This correlated with PCFT bio-tinylated at the cell surface. In contrast, all D109 mutants, including D109E, lacked function irrespective of pH (4.5, 5.5, and 7.4) or substrate concentration (0.5-100 ?M), despite surface expression comparable to wild-type PCFT. Hence, D156 plays a critical role in PCFT protein stability, and D109, located in the first intracellular loop between the second and third transmembrane domains, is absolutely required for PCFT function.
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Project description:Hereditary folate malabsorption (OMIM 229050) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter gene (pcft/SLC46A1) resulting in impaired folate transport across the intestine and into the central nervous system. We report a novel, homozygous, deletion mutation in a child of Nicaraguan descent in exon 2 (c.558-588 del, ss778190447) at amino acid position I188 resulting in a frameshift with a premature stop.
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Project description:The proton-coupled folate transporter (PCFT-SLC46A1) is required for intestinal folate absorption and is mutated in the autosomal recessive disorder, hereditary folate malabsorption (HFM). This report characterizes properties and requirements of the R376 residue in PCFT function, including a R376Q mutant associated with HFM. Gln, Cys, and Ala substitutions resulted in markedly impaired transport of 5-formyltetrahydrofolate (5-FTHF) and 5-methyltetrahydrofolate (5-MTHF) due to an increase in K(m) and decrease in V(max) in HeLa R1-11 transfectants lacking endogenous folate transport function. In contrast, although the influx K(m) for pemetrexed was increased, transport was fully preserved at saturating concentrations and enhanced for the like-charged R376K- and R376H-PCFT. Pemetrexed and 5-FTHF influx mediated by R376Q-PCFT was markedly decreased at pH 5.5 compared with wild-type PCFT. However, while pemetrexed transport was substantially preserved at low pH (4.5-5.0), 5-FTHF transport remained very low. Electrophysiological studies in Xenopus oocytes demonstrated that 1) the R376Q mutant, like wild-type PCFT, transports protons in the absence of folate substrate, and in this respect has channel-like properties; and 2) the influx K(m) mediated by R376Q-PCFT is increased for 5-MTHF, 5-FTHF, and pemetrexed. The data suggest that mutation of the R376 residue to Gln impairs proton binding which, in turn, modulates the folate-binding pocket and depresses the rate of conformational alteration of the carrier, a change that appears to be, in part, substrate dependent.
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Project description:Hereditary folate malabsorption is a rare autosomal recessive disorder caused by impaired active folate transport across membranes and into the central nervous system due to loss-of-function mutations in proton-coupled folate transporter (PCFT). Newborns with this condition have initially normal folate stores, but as they are unable to absorb dietary folate and use rapidly their stores because of their growth demands, symptoms appear in the early infancy. Significant neurological morbidity usually follows the initial non-specific clinical presentation and delayed initiation of treatment. High dose oral and parenteral folinic acid treatment have been previously reported in literature to improve the clinical outcome without achieving optimal cerebrospinal fluid (CSF) folate levels though. The active isomer of 5-formyltetrahydrofolate, also known as levofolinic acid, is available for administration. We report our experience in achieving normal (age dependent) CSF 5-Methyltetrahydrofolate (5-MTHF) levels following daily intramuscular administration of levofolinic acid in three patients with HFM. Follow-up assessment with repeated lumbar punctures has shown a stabilization of 5-MTHF levels within normal range. Clinical features and brain MRI findings had as well either improvement or stabilization. To the best of our knowledge, we provide as well for the first time data in regard to the im levofolinate treatment dosage.
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Project description: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.
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