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'''Hereditary folate malabsorption (HFM)''' is a rare autosomal recessive disorder caused by mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.
'''Hereditary folate malabsorption (HFM - OMIM #229050)''' is a rare autosomal recessive disorder caused by caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.


==Clinical presentation==
==Clinical Presentation==
Affected infants present within a few months after birth with failure to thrive, macrocytic anemia and developmental delays. There can be (i) pancytopenia, (ii) diarrhea and/or mucositis and/or (iii) immune deficiency due to T-cell dysfunction and hypoimmunoglobulinemia resulting in pneumonia usually due to Pneumocystitis jerovici.<ref name="geller 2002">{{cite journal|last1=Geller|first1=J|last2=Kronn|first2=D|last3=Jayabose|first3=S|last4=Sandoval|first4=C|title=Hereditary folate malabsorption: family report and review of the literature.|journal=Medicine|date=January 2002|volume=81|issue=1|pages=51–68|pmid=11807405}}</ref> Recently, several infants with this immune deficiency syndrome were described.<ref name="Borzutzky Clinical immunology 2009">{{cite journal|last1=Borzutzky|first1=A|last2=Crompton|first2=B|last3=Bergmann|first3=AK|last4=Giliani|first4=S|last5=Baxi|first5=S|last6=Martin|first6=M|last7=Neufeld|first7=EJ|last8=Notarangelo|first8=LD|title=Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter.|journal=Clinical immunology (Orlando, Fla.)|date=December 2009|volume=133|issue=3|pages=287–94|pmid=19740703}}</ref><ref name="Kishimoto Clinical immunology 2014">{{cite journal|last1=Kishimoto|first1=K|last2=Kobayashi|first2=R|last3=Sano|first3=H|last4=Suzuki|first4=D|last5=Maruoka|first5=H|last6=Yasuda|first6=K|last7=Chida|first7=N|last8=Yamada|first8=M|last9=Kobayashi|first9=K|title=Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.|journal=Clinical immunology (Orlando, Fla.)|date=July 2014|volume=153|issue=1|pages=17–22|pmid=24691418}}</ref><ref name="Erlacher Pediatric 2015">{{cite journal|last1=Erlacher|first1=M|last2=Grünert|first2=SC|last3=Cseh|first3=A|last4=Steinfeld|first4=R|last5=Salzer|first5=U|last6=Lausch|first6=E|last7=Nosswitz|first7=U|last8=Dückers|first8=G|last9=Niehues|first9=T|last10=Ehl|first10=S|last11=Niemeyer|first11=CM|last12=Speckmann|first12=C|title=Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption.|journal=Pediatric blood & cancer|date=June 2015|volume=62|issue=6|pages=1091–4|pmid=25504888}}</ref> Untreated, or with inadequate treatment, there are progressive systemic and neurological signs with a spectrum of manifestations including seizures that are often intractable. Females with HFM are fertile and, if folate sufficient during pregnancy, have normal offspring. Subjects that carry one mutated PCFT allele are normal. The genomic and clinical features of HFM, along with its treatment, were recently reviewed.<ref name="GeneReviews">{{cite journal|last1=Diop-Bove|first1=N|last2=Kronn|first2=D|last3=Goldman|first3=ID|last4=Pagon|first4=RA|last5=Adam|first5=MP|last6=Ardinger|first6=HH|last7=Wallace|first7=SE|last8=Amemiya|first8=A|last9=Bean|first9=LJH|last10=Bird|first10=TD|last11=Dolan|first11=CR|last12=Fong|first12=CT|last13=Smith|first13=RJH|last14=Stephens|first14=K|title=Hereditary Folate Malabsorption|date=1993|pmid=20301716}}</ref>
Affected infants present within a few months after birth with failure to thrive and severe [[folate deficiency]] manifested as [[macrocytic anemia]] and developmental delays. There can be (i) pancytopenia, (ii) diarrhea and/or mucositis and/or (iii) immune deficiency due to T-cell dysfunction and hypoimmunoglobulinemia resulting in pneumonia usually due to [[Pneumocystis jirovecii]].<ref name="geller 2002">{{cite journal|last1=Geller|first1=J|last2=Kronn|first2=D|last3=Jayabose|first3=S|last4=Sandoval|first4=C|title=Hereditary folate malabsorption: family report and review of the literature.|journal=Medicine|date=January 2002|volume=81|issue=1|pages=51–68|pmid=11807405}}</ref> Recently, several infants with the immune deficiency syndrome were described.<ref name="Borzutzky Clinical immunology 2009">{{cite journal|last1=Borzutzky|first1=A|last2=Crompton|first2=B|last3=Bergmann|first3=AK|last4=Giliani|first4=S|last5=Baxi|first5=S|last6=Martin|first6=M|last7=Neufeld|first7=EJ|last8=Notarangelo|first8=LD|title=Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter.|journal=Clinical immunology (Orlando, Fla.)|date=December 2009|volume=133|issue=3|pages=287–94|pmid=19740703}}</ref><ref name="Kishimoto Clinical immunology 2014">{{cite journal|last1=Kishimoto|first1=K|last2=Kobayashi|first2=R|last3=Sano|first3=H|last4=Suzuki|first4=D|last5=Maruoka|first5=H|last6=Yasuda|first6=K|last7=Chida|first7=N|last8=Yamada|first8=M|last9=Kobayashi|first9=K|title=Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption.|journal=Clinical immunology (Orlando, Fla.)|date=July 2014|volume=153|issue=1|pages=17–22|pmid=24691418}}</ref><ref name="Erlacher Pediatric 2015">{{cite journal|last1=Erlacher|first1=M|last2=Grünert|first2=SC|last3=Cseh|first3=A|last4=Steinfeld|first4=R|last5=Salzer|first5=U|last6=Lausch|first6=E|last7=Nosswitz|first7=U|last8=Dückers|first8=G|last9=Niehues|first9=T|last10=Ehl|first10=S|last11=Niemeyer|first11=CM|last12=Speckmann|first12=C|title=Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption.|journal=Pediatric blood & cancer|date=June 2015|volume=62|issue=6|pages=1091–4|pmid=25504888}}</ref> Untreated, or with inadequate treatment, there are progressive systemic and neurological signs with a spectrum of manifestations including seizures that are often intractable. Females with HFM are fertile and, if folate sufficient during pregnancy, have normal offspring. Subjects that carry one mutated PCFT allele are normal. The genomic and clinical features of HFM were recently reviewed.<ref name="geller 2002"/><ref name="Erlacher Pediatric 2015"/><ref name="GeneReviews">{{cite journal|last1=Diop-Bove|first1=N|last2=Kronn|first2=D|last3=Goldman|first3=ID|last4=Pagon|first4=RA|last5=Adam|first5=MP|last6=Ardinger|first6=HH|last7=Wallace|first7=SE|last8=Amemiya|first8=A|last9=Bean|first9=LJH|last10=Bird|first10=TD|last11=Dolan|first11=CR|last12=Fong|first12=CT|last13=Smith|first13=RJH|last14=Stephens|first14=K|title=Hereditary Folate Malabsorption|date=1993|pmid=20301716}}</ref>


==Pathophysiology==
==Pathophysiology and Diagnosis==
Extensive clinical studies established that HFM is due to (i) impaired intestinal absorption of folates and (ii) impaired transport of folates across the blood-brain barrier into the cerebrospinal fluid (CSF) presumably at the level of the choroid plexus.<ref name="geller 2002"/><ref>{{cite journal|last1=Lanzkowsky|first1=P|last2=Erlandson|first2=ME|last3=Bezan|first3=AI|title=Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification.|journal=Blood|date=October 1969|volume=34|issue=4|pages=452–65|pmid=4980683}}</ref><ref>{{cite journal|last1=Poncz|first1=M|last2=Colman|first2=N|last3=Herbert|first3=V|last4=Schwartz|first4=E|last5=Cohen|first5=AR|title=Therapy of congenital folate malabsorption.|journal=The Journal of pediatrics|date=January 1981|volume=98|issue=1|pages=76–9|pmid=6969796}}</ref><ref>{{cite journal|last1=Urbach|first1=J|last2=Abrahamov|first2=A|last3=Grossowicz|first3=N|title=Congenital isolated folic acid malabsorption.|journal=Archives of disease in childhood|date=January 1987|volume=62|issue=1|pages=78–80|pmid=3813642}}</ref> Hence, patients with HFM have very low or undetectable folate blood levels. When a modest dose of a folate is given by mouth, there is impaired intestinal folate absorption without other signs of malabsorption. The CSF folate level is often undetectable at the time of diagnosis. Even when the blood folate level is corrected the CSF folate level remains very low, consistent with impaired transport across the choroid plexus. The normal CSF folate level in children over the first three years of life is in the 75 to 150 nM range. In subjects with HFM, It is very difficult to bring the CSF folate level into the normal range even with substantial doses of parenteral folate (see below).
Extensive clinical studies established that HFM is due to (i) impaired intestinal absorption of folates and (ii) impaired transport of folates across the blood-choroid plexus-[[cerebrospinal fluid]] (CSF) barrier.<ref name="geller 2002"/><ref name="Lanzkowsky Blood 1969">{{cite journal|last1=Lanzkowsky|first1=P|last2=Erlandson|first2=ME|last3=Bezan|first3=AI|title=Isolated defect of folic acid absorption associated with mental retardation and cerebral calcification.|journal=Blood|date=October 1969|volume=34|issue=4|pages=452–65|pmid=4980683}}</ref><ref name="Poncz Pediatrics 1981">{{cite journal|last1=Poncz|first1=M|last2=Colman|first2=N|last3=Herbert|first3=V|last4=Schwartz|first4=E|last5=Cohen|first5=AR|title=Therapy of congenital folate malabsorption.|journal=The Journal of pediatrics|date=January 1981|volume=98|issue=1|pages=76–9|pmid=6969796}}</ref><ref name="Urbach Archives 1987">{{cite journal|last1=Urbach|first1=J|last2=Abrahamov|first2=A|last3=Grossowicz|first3=N|title=Congenital isolated folic acid malabsorption.|journal=Archives of disease in childhood|date=January 1987|volume=62|issue=1|pages=78–80|pmid=3813642}}</ref> Hence, patients with HFM have very low or undetectable folate blood levels. When a modest dose of a folate is given by mouth, there is impaired intestinal folate absorption without other signs of malabsorption. The CSF folate level is usually undetectable at the time of diagnosis. Even when the blood folate level is corrected, or far above normal, the CSF folate level remains low, consistent with impaired transport across the choroid plexus. The normal CSF folate level in children over the first three years of life is in the 75 to 150 nM range.<ref name="Ormazabal Clinica 2006">{{cite journal|last1=Ormazabal|first1=A|last2=García-Cazorla|first2=A|last3=Pérez-Dueñas|first3=B|last4=Gonzalez|first4=V|last5=Fernández-Alvarez|first5=E|last6=Pineda|first6=M|last7=Campistol|first7=J|last8=Artuch|first8=R|title=Determination of 5-methyltetrahydrofolate in cerebrospinal fluid of paediatric patients: reference values for a paediatric population.|journal=Clinica chimica acta; international journal of clinical chemistry|date=September 2006|volume=371|issue=1-2|pages=159-62|pmid=16624264}}</ref><ref name="Verbeek Molecular genetics 2008">{{cite journal|last1=Verbeek|first1=MM|last2=Blom|first2=AM|last3=Wevers|first3=RA|last4=Lagerwerf|first4=AJ|last5=van de Geer|first5=J|last6=Willemsen|first6=MA|title=Technical and biochemical factors affecting cerebrospinal fluid 5-MTHF, biopterin and neopterin concentrations.|journal=Molecular genetics and metabolism|date=November 2008|volume=95|issue=3|pages=127-32|pmid=18722797}}</ref> In subjects with HFM it is very difficult indeed, rarely possible, to bring the CSF folate level into the normal range even with substantial doses of parenteral folate<ref name="Torres JIMD 2015">{{cite journal|last1=Torres|first1=A|last2=Newton|first2=SA|last3=Crompton|first3=B|last4=Borzutzky|first4=A|last5=Neufeld|first5=EJ|last6=Notarangelo|first6=L|last7=Berry|first7=GT|title=CSF 5-Methyltetrahydrofolate Serial Monitoring to Guide Treatment of Congenital Folate Malabsorption Due to Proton-Coupled Folate Transporter (PCFT) Deficiency.|journal=JIMD reports|date=26 May 2015|pmid=26006721}}</ref> (see below).


==Molecular Pathogenesis==
==Molecular Pathogenesis==
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==Incidence==
==Incidence==
As of June 2014 (the latest update on HFM<ref name="GeneReviews"/> in [[GeneReviews]]) a total of 32 families had been reported with a clinical diagnosis of HFM of which there was genotypic confirmation in 24 families. Since then, another two confirmed cases have been reported<ref name="Kishimoto Clinical immunology 2014"/><ref name="Erlacher Pediatric 2015"/> and an additional case was reported based on a clinical diagnosis alone.<ref>{{cite journal|last1=Ahmad|first1=I|last2=Mukhtar|first2=G|last3=Iqbal|first3=J|last4=Ali|first4=SW|title=Hereditary folate malabsorption with extensive intracranial calcification.|journal=Indian pediatrics|date=January 2015|volume=52|issue=1|pages=67–8|pmid=25638192}}</ref> Most cases emerge from consanguineous parents with homozygous mutations. There are three instances of HFM from non-consanguineous parents in which there were heterozygous mutations. HFM cases are world-wide with mostly private mutations. However, a number of families of Puerto Rican ancestry have been reported with a common pathogenic variant at a splice receptor site resulting in the deletion of exon 3 and the absence of transport function.<ref name="Borzutzky Clinical immunology 2009"/><ref name="GeneReviews"/><ref name="Qiu Cell 2006"/><ref>{{cite journal|last1=Santiago-Borrero|first1=PJ|last2=Santini R|first2=Jr|last3=Pérez-Santiago|first3=E|last4=Maldonado|first4=N|title=Congenital isolated defect of folic acid absorption.|journal=The Journal of pediatrics|date=March 1973|volume=82|issue=3|pages=450–5|pmid=4540608}}</ref> A subsequent population-based studies of newborn infants in Puerto Rico identified the presence of the same variant on the island.<ref>{{cite journal|last1=Mahadeo|first1=KM|last2=Diop-Bove|first2=N|last3=Ramirez|first3=SI|last4=Cadilla|first4=CL|last5=Rivera|first5=E|last6=Martin|first6=M|last7=Lerner|first7=NB|last8=DiAntonio|first8=L|last9=Duva|first9=S|last10=Santiago-Borrero|first10=PJ|last11=Goldman|first11=ID|title=Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico.|journal=The Journal of pediatrics|date=October 2011|volume=159|issue=4|pages=623–7.e1|pmid=21489556}}</ref> Most of the pathogenic variants result in a complete loss of the PCFT protein or point mutations that result in the complete loss of function. However, there was sufficient residual function with some of the point mutants to allow characterization of the transport defect.<ref>{{cite journal|last1=Shin|first1=DS|last2=Zhao|first2=R|last3=Yap|first3=EH|last4=Fiser|first4=A|last5=Goldman|first5=ID|title=A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding.|journal=American journal of physiology. Cell physiology|date=1 May 2012|volume=302|issue=9|pages=C1405-12|pmid=22345511}}</ref><ref>{{cite journal|last1=Shin|first1=DS|last2=Mahadeo|first2=K|last3=Min|first3=SH|last4=Diop-Bove|first4=N|last5=Clayton|first5=P|last6=Zhao|first6=R|last7=Goldman|first7=ID|title=Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption.|journal=Molecular genetics and metabolism|date=May 2011|volume=103|issue=1|pages=33–7|pmid=21333572}}</ref>
As of June 2014 (the latest update on HFM<ref name="GeneReviews"/> in [[GeneReviews]]) a total of 32 families had been reported with a clinical diagnosis of HFM of which there was genotypic confirmation in 24 families. Since then, another two confirmed cases have been reported<ref name="Kishimoto Clinical immunology 2014"/><ref name="Erlacher Pediatric 2015"/> and an additional case was reported based on a clinical diagnosis alone.<ref>{{cite journal|last1=Ahmad|first1=I|last2=Mukhtar|first2=G|last3=Iqbal|first3=J|last4=Ali|first4=SW|title=Hereditary folate malabsorption with extensive intracranial calcification.|journal=Indian pediatrics|date=January 2015|volume=52|issue=1|pages=67–8|pmid=25638192}}</ref> Most cases emerge from consanguineous parents with homozygous mutations. There are three instances of HFM from non-consanguineous parents in which there were heterozygous mutations. HFM cases are world-wide with mostly private mutations. However, a number of families of Puerto Rican ancestry have been reported with a common pathogenic variant at a splice receptor site resulting in the deletion of exon 3 and the absence of transport function.<ref name="Borzutzky Clinical immunology 2009"/><ref name="GeneReviews"/><ref name="Qiu Cell 2006"/><ref>{{cite journal|last1=Santiago-Borrero|first1=PJ|last2=Santini R|first2=Jr|last3=Pérez-Santiago|first3=E|last4=Maldonado|first4=N|title=Congenital isolated defect of folic acid absorption.|journal=The Journal of pediatrics|date=March 1973|volume=82|issue=3|pages=450–5|pmid=4540608}}</ref> A subsequent population-based study of newborn infants in Puerto Rico identified the presence of the same variant on the island.<ref>{{cite journal|last1=Mahadeo|first1=KM|last2=Diop-Bove|first2=N|last3=Ramirez|first3=SI|last4=Cadilla|first4=CL|last5=Rivera|first5=E|last6=Martin|first6=M|last7=Lerner|first7=NB|last8=DiAntonio|first8=L|last9=Duva|first9=S|last10=Santiago-Borrero|first10=PJ|last11=Goldman|first11=ID|title=Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico.|journal=The Journal of pediatrics|date=October 2011|volume=159|issue=4|pages=623–7.e1|pmid=21489556}}</ref> Most of the pathogenic variants result in a complete loss of the PCFT protein or point mutations that result in the complete loss of function. However, residual function can be detected with some of the point mutants.<ref>{{cite journal|last1=Mahadeo|first1=K|last2=Diop-Bove|first2=N|last3=Shin|first3=D|last4=Unal|first4=ES|last5=Teo|first5=J|last6=Zhao|first6=R|last7=Chang|first7=MH|last8=Fulterer|first8=A|last9=Romero|first9=MF|last10=Goldman|first10=ID|title=Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption.|journal=American journal of physiology. Cell physiology|date=November 2010|volume=299|issue=5|pages=C1153-61|pmid=20686069}}</ref>


==Distinguishing between HFM and cerebral folate deficiency==
==Distinguishing between HFM and Cerebral Folate Deficiency==
HFM must be distinguished from cerebral folate deficiency (CFD)– a condition in which there is normal intestinal folate absorption, without systemic folate deficiency, but a decrease in CSF folate levels. This can accompany a variety of disorders.<ref>{{cite journal|last1=Hyland|first1=K|last2=Shoffner|first2=J|last3=Heales|first3=SJ|title=Cerebral folate deficiency.|journal=Journal of inherited metabolic disease|date=October 2010|volume=33|issue=5|pages=563–70|pmid=20668945}}</ref> One form of CFD is due to loss-of-mutations in folate receptor-α, (FRα), which transports folates via an endocytic process.<ref>{{cite journal|last1=Steinfeld|first1=R|last2=Grapp|first2=M|last3=Kraetzner|first3=R|last4=Dreha-Kulaczewski|first4=S|last5=Helms|first5=G|last6=Dechent|first6=P|last7=Wevers|first7=R|last8=Grosso|first8=S|last9=Gärtner|first9=J|title=Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.|journal=American journal of human genetics|date=September 2009|volume=85|issue=3|pages=354–63|pmid=19732866}}</ref><ref>{{cite journal|last1=Grapp|first1=M|last2=Just|first2=IA|last3=Linnankivi|first3=T|last4=Wolf|first4=P|last5=Lücke|first5=T|last6=Häusler|first6=M|last7=Gärtner|first7=J|last8=Steinfeld|first8=R|title=Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.|journal=Brain : a journal of neurology|date=July 2012|volume=135|issue=Pt 7|pages=2022–31|pmid=22586289}}</ref><ref>{{cite journal|last1=Toelle|first1=SP|last2=Wille|first2=D|last3=Schmitt|first3=B|last4=Scheer|first4=I|last5=Thöny|first5=B|last6=Plecko|first6=B|title=Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency.|journal=Epileptic disorders : international epilepsy journal with videotape|date=March 2014|volume=16|issue=1|pages=88–92|pmid=24556562}}</ref> While PCFT is expressed primarily at the basolateral membrane of choroid plexus, FRα, is expressed primarily at the apical brush-border membrane.<ref>{{cite journal|last1=Zhao|first1=R|last2=Min|first2=SH|last3=Wang|first3=Y|last4=Campanella|first4=E|last5=Low|first5=PS|last6=Goldman|first6=ID|title=A role for the proton-coupled folate transporter (PCFT-SLC46A1) in folate receptor-mediated endocytosis.|journal=The Journal of biological chemistry|date=13 February 2009|volume=284|issue=7|pages=4267–74|pmid=19074442}}</ref><ref name="Zhao Annu Rev Nutr 2011">{{cite journal|last1=Zhao|first1=R|last2=Diop-Bove|first2=N|last3=Visentin|first3=M|last4=Goldman|first4=ID|title=Mechanisms of membrane transport of folates into cells and across epithelia.|journal=Annual review of nutrition|date=21 August 2011|volume=31|pages=177–201|pmid=21568705}}</ref> Unlike subjects with HFM, patients with CFD present with neurological signs a few years after birth. The basis for the delay in the appearance of clinical manifestations due to loss of FRα function is not clear; the normal blood folate levels may be protective, although for a limited time.
HFM must be distinguished from cerebral folate deficiency (CFD)– a condition in which there is normal intestinal folate absorption, without systemic folate deficiency, but a decrease in CSF folate levels. This can accompany a variety of disorders.<ref>{{cite journal|last1=Hyland|first1=K|last2=Shoffner|first2=J|last3=Heales|first3=SJ|title=Cerebral folate deficiency.|journal=Journal of inherited metabolic disease|date=October 2010|volume=33|issue=5|pages=563–70|pmid=20668945}}</ref> One form of CFD is due to loss-of-mutations in folate receptor-α, (FRα), which transports folates via an endocytic process.<ref>{{cite journal|last1=Steinfeld|first1=R|last2=Grapp|first2=M|last3=Kraetzner|first3=R|last4=Dreha-Kulaczewski|first4=S|last5=Helms|first5=G|last6=Dechent|first6=P|last7=Wevers|first7=R|last8=Grosso|first8=S|last9=Gärtner|first9=J|title=Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism.|journal=American journal of human genetics|date=September 2009|volume=85|issue=3|pages=354–63|pmid=19732866}}</ref><ref>{{cite journal|last1=Grapp|first1=M|last2=Just|first2=IA|last3=Linnankivi|first3=T|last4=Wolf|first4=P|last5=Lücke|first5=T|last6=Häusler|first6=M|last7=Gärtner|first7=J|last8=Steinfeld|first8=R|title=Molecular characterization of folate receptor 1 mutations delineates cerebral folate transport deficiency.|journal=Brain : a journal of neurology|date=July 2012|volume=135|issue=Pt 7|pages=2022–31|pmid=22586289}}</ref><ref>{{cite journal|last1=Toelle|first1=SP|last2=Wille|first2=D|last3=Schmitt|first3=B|last4=Scheer|first4=I|last5=Thöny|first5=B|last6=Plecko|first6=B|title=Sensory stimulus-sensitive drop attacks and basal ganglia calcification: new findings in a patient with FOLR1 deficiency.|journal=Epileptic disorders : international epilepsy journal with videotape|date=March 2014|volume=16|issue=1|pages=88–92|pmid=24556562}}</ref> While PCFT is expressed primarily at the basolateral membrane of the choroid plexus, FRα, is expressed primarily at the apical brush-border membrane.<ref name="Grapp Nature communications 2013">{{cite journal|last1=Grapp|first1=M|last2=Wrede|first2=A|last3=Schweizer|first3=M|last4=Hüwel|first4=S|last5=Galla|first5=HJ|last6=Snaidero|first6=N|last7=Simons|first7=M|last8=Bückers|first8=J|last9=Low|first9=PS|last10=Urlaub|first10=H|last11=Gärtner|first11=J|last12=Steinfeld|first12=R|title=Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma.|journal=Nature communications|date=2013|volume=4|pages=2123|pmid=23828504}}</ref> Unlike subjects with HFM, patients with CFD present with neurological signs a few years after birth. The basis for the delay in the appearance of clinical manifestations due to loss of FRα function is not clear; the normal blood folate levels may be protective, although for a limited time.


==PCFT: Physiological Properties and Expression==
==PCFT: Physiological Properties and Expression==
PCFT consists of 459 amino acids, with five exons, and a MW of approximately 50kDa. The secondary structure has been established and consists of twelve transmembrane domains with the N- and C- termini directed into the cytoplasm. The properties of this transporter and its physiological and pharmacological roles were recently reviewed.<ref name="Zhao Annu Rev Nutr 2011"/><ref name="Visentin Physiol 2014">{{cite journal|last1=Visentin|first1=M|last2=Diop-Bove|first2=N|last3=Zhao|first3=R|last4=Goldman|first4=ID|title=The intestinal absorption of folates.|journal=Annual review of physiology|date=2014|volume=76|pages=251–74|pmid=24512081}}</ref><ref>{{cite journal|last1=Zhao|first1=R|last2=Goldman|first2=ID|title=Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors.|journal=Molecular aspects of medicine|date= 2013|volume=34|issue=2-3|pages=373–85|pmid=23506878}}</ref><ref>{{cite journal|last1=Zhao|first1=R|last2=Matherly|first2=LH|last3=Goldman|first3=ID|title=Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.|journal=Expert reviews in molecular medicine|date=28 January 2009|volume=11|pages=e4|pmid=19173758}}</ref><ref>{{cite journal|last1=Matherly|first1=LH|last2=Wilson|first2=MR|last3=Hou|first3=Z|title=The major facilitative folate transporters solute carrier 19A1 and solute carrier 46A1: biology and role in antifolate chemotherapy of cancer.|journal=Drug metabolism and disposition: the biological fate of chemicals|date=April 2014|volume=42|issue=4|pages=632–49|pmid=24396145}}</ref> Elements of PCFT regulation have been described and include Vitamin D and NRF1 response elements.<ref>{{cite journal|last1=Diop-Bove|first1=NK|last2=Wu|first2=J|last3=Zhao|first3=R|last4=Locker|first4=J|last5=Goldman|first5=ID|title=Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line.|journal=Molecular cancer therapeutics|date=August 2009|volume=8|issue=8|pages=2424–31|pmid=19671745}}</ref><ref>{{cite journal|last1=Gonen|first1=N|last2=Assaraf|first2=YG|title=The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1.|journal=The Journal of biological chemistry|date=29 October 2010|volume=285|issue=44|pages=33602–13|pmid=20724482}}</ref><ref>{{cite journal|last1=Eloranta|first1=JJ|last2=Zaïr|first2=ZM|last3=Hiller|first3=C|last4=Häusler|first4=S|last5=Stieger|first5=B|last6=Kullak-Ublick|first6=GA|title=Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter.|journal=Molecular pharmacology|date=November 2009|volume=76|issue=5|pages=1062–71|pmid=19666701}}</ref> PCFT operates most efficiently when there is a strong transmembrane pH gradient. Under these conditions transport of a folate molecule across the cell membrane is accompanied by a sufficient number of protons to result a positive charge and current mediated by the ternary carrier complex. It is the pH gradient present across the apical brush-border membrane of the proximal jejunum, where PCFT is highly expressed, that drives intestinal folate absorption. PCFT is expressed to a lesser extent elsewhere in the small and large intestine along with the canalicular membrane of the hepatic sinusoid and in the apical brush-border membrane of the proximal tubule of the kidney. However, its function at these latter sites is unclear.<ref name="Zhao Annu Rev Nutr 2011"/> As indicated above, PCFT is also expressed at the basolateral membrane of ependymal cells of the choroid plexus where it presumably plays a role in transport of folates into the CSF, although the extent to which a pH gradient might be present at that membrane interface is not clear.<ref name="Zhao Annu Rev Nutr 2011"/><ref name="Visentin Physiol 2014"/>
PCFT is located on chromosome 17q11.2 and consists of 459 amino acids, with five exons, and a MW of approximately 50kDa.<ref name="Qiu Cell 2006"/> The secondary structure has been established and consists of twelve transmembrane domains with the N- and C- termini directed into the cytoplasm.<ref>{{cite journal|last1=Duddempudi|first1=PK|last2=Goyal|first2=R|last3=Date|first3=SS|last4=Jansen|first4=M|title=Delineating the extracellular water-accessible surface of the proton-coupled folate transporter.|journal=PloS one|date=2013|volume=8|issue=10|pages=e78301|pmid=24205192}}</ref><ref>{{cite journal|last1=Zhao|first1=R|last2=Unal|first2=ES|last3=Shin|first3=DS|last4=Goldman|first4=ID|title=Membrane topological analysis of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method.|journal=Biochemistry|date=6 April 2010|volume=49|issue=13|pages=2925-31|pmid=20225891}}</ref> The properties of this transporter and its physiological and pharmacological roles were recently reviewed.<ref>{{cite journal|last1=Zhao|first1=R|last2=Goldman|first2=ID|title=Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors.|journal=Molecular aspects of medicine|date= 2013|volume=34|issue=2-3|pages=373–85|pmid=23506878}}</ref><ref>{{cite journal|last1=Desmoulin|first1=SK|last2=Hou|first2=Z|last3=Gangjee|first3=A|last4=Matherly|first4=LH|title=The human proton-coupled folate transporter: Biology and therapeutic applications to cancer.|journal=Cancer biology & therapy|date=December 2012|volume=13|issue=14|pages=1355-73|pmid=22954694}}</ref> Elements of PCFT regulation have been described and include the minimal promoter,<ref>{{cite journal|last1=Stark|first1=M|last2=Gonen|first2=N|last3=Assaraf|first3=YG|title=Functional elements in the minimal promoter of the human proton-coupled folate transporter.|journal=Biochemical and biophysical research communications|date=9 October 2009|volume=388|issue=1|pages=79-85|pmid=19643086}}</ref><ref>{{cite journal|last1=Diop-Bove|first1=NK|last2=Wu|first2=J|last3=Zhao|first3=R|last4=Locker|first4=J|last5=Goldman|first5=ID|title=Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line.|journal=Molecular cancer therapeutics|date=August 2009|volume=8|issue=8|pages=2424-31|pmid=19671745}}</ref> Vitamin D<ref>{{cite journal|last1=Eloranta|first1=JJ|last2=Zaïr|first2=ZM|last3=Hiller|first3=C|last4=Häusler|first4=S|last5=Stieger|first5=B|last6=Kullak-Ublick|first6=GA|title=Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter.|journal=Molecular pharmacology|date=November 2009|volume=76|issue=5|pages=1062-71|pmid=19666701}}</ref> and NRF1<ref>{{cite journal|last1=Gonen|first1=N|last2=Assaraf|first2=YG|title=The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1.|journal=The Journal of biological chemistry|date=29 October 2010|volume=285|issue=44|pages=33602-13|pmid=20724482}}</ref> response elements. PCFT operates most efficiently when there is a strong transmembrane pH gradient. Under these conditions transport of a folate molecule across the cell membrane is accompanied by a sufficient number of protons to result a positive charge and current mediated by the ternary carrier complex.<ref name="Qiu Cell 2006"/><ref>{{cite journal|last1=Umapathy|first1=NS|last2=Gnana-Prakasam|first2=JP|last3=Martin|first3=PM|last4=Mysona|first4=B|last5=Dun|first5=Y|last6=Smith|first6=SB|last7=Ganapathy|first7=V|last8=Prasad|first8=PD|title=Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types.|journal=Investigative ophthalmology & visual science|date=November 2007|volume=48|issue=11|pages=5299-305|pmid=17962486}}</ref> It is the pH gradient present across the apical brush-border membrane of the proximal jejunum,<ref name="Said Pediatric 1987">{{cite journal|last1=Said|first1=HM|last2=Smith|first2=R|last3=Redha|first3=R|title=Studies on the intestinal surface acid microclimate: developmental aspects.|journal=Pediatric research|date=November 1987|volume=22|issue=5|pages=497-9|pmid=3684377}}</ref> where PCFT is highly expressed, that drives intestinal folate absorption.<ref name="Said Pediatric 1987"/><ref name="Visentin Physiol 2014">{{cite journal|last1=Visentin|first1=M|last2=Diop-Bove|first2=N|last3=Zhao|first3=R|last4=Goldman|first4=ID|title=The intestinal absorption of folates.|journal=Annual review of physiology|date=2014|volume=76|pages=251-74|pmid=24512081}}</ref> PCFT is expressed to a lesser extent elsewhere in the small and large intestine along with the canalicular membrane of the hepatic sinusoid and in the apical brush-border membrane of the proximal tubule of the kidney. However, its function at these latter sites is unclear.<ref name="Zhao Annu Rev Nutr 2011">{{cite journal|last1=Zhao|first1=R|last2=Diop-Bove|first2=N|last3=Visentin|first3=M|last4=Goldman|first4=ID|title=Mechanisms of membrane transport of folates into cells and across epithelia.|journal=Annual review of nutrition|date=21 August 2011|volume=31|pages=177-201|pmid=21568705}}</ref> As indicated above, PCFT is also expressed at the basolateral membrane of ependymal cells of the choroid plexus where it presumably plays a role in transport of folates into the CSF.<ref name="Zhao Annu Rev Nutr 2011"/>


==Treatment==
==Treatment==
Because HFM is a rare disorder, there are no studies that define its optimal treatment. Correction of the systemic folate deficiency, with the normalization of folate blood levels, is easily achieved with high doses of oral folates or much smaller doses of parenteral folate. This will rapidly correct the anemia, immune deficiency and GI signs. The challenge is to achieve adequate treatment of the neurological component of HFM. It is essential that the folate dose is sufficiently high to achieve CSF folate levels as close as possible to the normal range for the age of the child. This requires close monitoring of the CSF folate level. The physiological folate is 5-methyltetrahydrofolate but the oral formulation available is insufficient for treatment of this disorder. The optimal folate at this time is 5-formyltetrahydrofolate which, after administration, is converted to 5-methyltetrahydrofolate in the liver. The racemic mixture of 5-formyltetrahydrofolate (leucovorin) is generally available; the active S-isomer may be obtained as well and may be the preferred therapeutic folate form. Folic acid should not be used for the treatment of HFM. Folic acid is not a physiological folate. It binds tightly to, and may impede, FRα-mediated endocytosis which plays an important role in the transport of folates across the choroid plexus into the CSF (see above).<ref name="Zhao Annu Rev Nutr 2011"/> For a further consideration of treatment see [[GeneReviews]].<ref name="GeneReviews"/>
Because HFM is a rare disorder, there are no studies that define its optimal treatment. Correction of the systemic folate deficiency, with the normalization of folate blood levels, is easily achieved with high doses of oral folates or much smaller doses of parenteral folate.<ref name="geller 2002"/><ref name="Lanzkowsky Blood 1969"/><ref name="Poncz Pediatrics 1981"/><ref name="Urbach Archives 1987"/> This will rapidly correct the anemia, immune deficiency and GI signs. The challenge is to achieve adequate treatment of the neurological component of HFM. It is essential that the folate dose is sufficiently high to achieve CSF folate levels as close as possible to the normal range for the age of the child.<ref name="Ormazabal Clinica 2006"/><ref name="Verbeek Molecular genetics 2008"/> This requires close monitoring of the CSF folate level.<ref name="Torres JIMD 2015"/> The physiological folate is 5-methyltetrahydrofolate but the oral formulation available is insufficient for treatment of this disorder and a parenteral form is not available. The optimal folate at this time is [[5-formyltetrahydrofolate]] which, after administration, is converted to 5-methyltetrahydrofolate. The racemic mixture of 5-formyltetrahydrofolate (leucovorin) is generally available; the active S-isomer, levoleucovorin, may be obtained as well. Parenteral administration is the optimal treatment if that is possible. Folic acid should not be used for the treatment of HFM. Folic acid is not a physiological folate. It binds tightly to, and may impede, FRα-mediated endocytosis which plays an important role in the transport of folates across the choroid plexus into the CSF (see above).<ref name="Grapp Nature communications 2013"/><ref name="Zhao Annu Rev Nutr 2011"/> For a further consideration of treatment see [[GeneReviews]].<ref name="GeneReviews"/>



==References==
==References==

Revision as of 14:37, 11 September 2015

Hereditary folate malabsorption (HFM - OMIM #229050) is a rare autosomal recessive disorder caused by caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.

Clinical Presentation

Affected infants present within a few months after birth with failure to thrive and severe folate deficiency manifested as macrocytic anemia and developmental delays. There can be (i) pancytopenia, (ii) diarrhea and/or mucositis and/or (iii) immune deficiency due to T-cell dysfunction and hypoimmunoglobulinemia resulting in pneumonia usually due to Pneumocystis jirovecii.[1] Recently, several infants with the immune deficiency syndrome were described.[2][3][4] Untreated, or with inadequate treatment, there are progressive systemic and neurological signs with a spectrum of manifestations including seizures that are often intractable. Females with HFM are fertile and, if folate sufficient during pregnancy, have normal offspring. Subjects that carry one mutated PCFT allele are normal. The genomic and clinical features of HFM were recently reviewed.[1][4][5]

Pathophysiology and Diagnosis

Extensive clinical studies established that HFM is due to (i) impaired intestinal absorption of folates and (ii) impaired transport of folates across the blood-choroid plexus-cerebrospinal fluid (CSF) barrier.[1][6][7][8] Hence, patients with HFM have very low or undetectable folate blood levels. When a modest dose of a folate is given by mouth, there is impaired intestinal folate absorption without other signs of malabsorption. The CSF folate level is usually undetectable at the time of diagnosis. Even when the blood folate level is corrected, or far above normal, the CSF folate level remains low, consistent with impaired transport across the choroid plexus. The normal CSF folate level in children over the first three years of life is in the 75 to 150 nM range.[9][10] In subjects with HFM it is very difficult indeed, rarely possible, to bring the CSF folate level into the normal range even with substantial doses of parenteral folate[11] (see below).

Molecular Pathogenesis

The molecular basis for HFM was established in 2006 with the identification of the proton-coupled folate transporter (PCFT) as the mechanism of intestinal absorption of folates and the detection of loss-of-function mutations in this transporter in subjects with a clinical diagnosis of HFM.[12][13] Hence, beyond the characteristic clinical features, genotyping is now available to establish the diagnosis of HFM.

Incidence

As of June 2014 (the latest update on HFM[5] in GeneReviews) a total of 32 families had been reported with a clinical diagnosis of HFM of which there was genotypic confirmation in 24 families. Since then, another two confirmed cases have been reported[3][4] and an additional case was reported based on a clinical diagnosis alone.[14] Most cases emerge from consanguineous parents with homozygous mutations. There are three instances of HFM from non-consanguineous parents in which there were heterozygous mutations. HFM cases are world-wide with mostly private mutations. However, a number of families of Puerto Rican ancestry have been reported with a common pathogenic variant at a splice receptor site resulting in the deletion of exon 3 and the absence of transport function.[2][5][12][15] A subsequent population-based study of newborn infants in Puerto Rico identified the presence of the same variant on the island.[16] Most of the pathogenic variants result in a complete loss of the PCFT protein or point mutations that result in the complete loss of function. However, residual function can be detected with some of the point mutants.[17]

Distinguishing between HFM and Cerebral Folate Deficiency

HFM must be distinguished from cerebral folate deficiency (CFD)– a condition in which there is normal intestinal folate absorption, without systemic folate deficiency, but a decrease in CSF folate levels. This can accompany a variety of disorders.[18] One form of CFD is due to loss-of-mutations in folate receptor-α, (FRα), which transports folates via an endocytic process.[19][20][21] While PCFT is expressed primarily at the basolateral membrane of the choroid plexus, FRα, is expressed primarily at the apical brush-border membrane.[22] Unlike subjects with HFM, patients with CFD present with neurological signs a few years after birth. The basis for the delay in the appearance of clinical manifestations due to loss of FRα function is not clear; the normal blood folate levels may be protective, although for a limited time.

PCFT: Physiological Properties and Expression

PCFT is located on chromosome 17q11.2 and consists of 459 amino acids, with five exons, and a MW of approximately 50kDa.[12] The secondary structure has been established and consists of twelve transmembrane domains with the N- and C- termini directed into the cytoplasm.[23][24] The properties of this transporter and its physiological and pharmacological roles were recently reviewed.[25][26] Elements of PCFT regulation have been described and include the minimal promoter,[27][28] Vitamin D[29] and NRF1[30] response elements. PCFT operates most efficiently when there is a strong transmembrane pH gradient. Under these conditions transport of a folate molecule across the cell membrane is accompanied by a sufficient number of protons to result a positive charge and current mediated by the ternary carrier complex.[12][31] It is the pH gradient present across the apical brush-border membrane of the proximal jejunum,[32] where PCFT is highly expressed, that drives intestinal folate absorption.[32][33] PCFT is expressed to a lesser extent elsewhere in the small and large intestine along with the canalicular membrane of the hepatic sinusoid and in the apical brush-border membrane of the proximal tubule of the kidney. However, its function at these latter sites is unclear.[34] As indicated above, PCFT is also expressed at the basolateral membrane of ependymal cells of the choroid plexus where it presumably plays a role in transport of folates into the CSF.[34]

Treatment

Because HFM is a rare disorder, there are no studies that define its optimal treatment. Correction of the systemic folate deficiency, with the normalization of folate blood levels, is easily achieved with high doses of oral folates or much smaller doses of parenteral folate.[1][6][7][8] This will rapidly correct the anemia, immune deficiency and GI signs. The challenge is to achieve adequate treatment of the neurological component of HFM. It is essential that the folate dose is sufficiently high to achieve CSF folate levels as close as possible to the normal range for the age of the child.[9][10] This requires close monitoring of the CSF folate level.[11] The physiological folate is 5-methyltetrahydrofolate but the oral formulation available is insufficient for treatment of this disorder and a parenteral form is not available. The optimal folate at this time is 5-formyltetrahydrofolate which, after administration, is converted to 5-methyltetrahydrofolate. The racemic mixture of 5-formyltetrahydrofolate (leucovorin) is generally available; the active S-isomer, levoleucovorin, may be obtained as well. Parenteral administration is the optimal treatment if that is possible. Folic acid should not be used for the treatment of HFM. Folic acid is not a physiological folate. It binds tightly to, and may impede, FRα-mediated endocytosis which plays an important role in the transport of folates across the choroid plexus into the CSF (see above).[22][34] For a further consideration of treatment see GeneReviews.[5]


References

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  2. ^ a b Borzutzky, A; Crompton, B; Bergmann, AK; Giliani, S; Baxi, S; Martin, M; Neufeld, EJ; Notarangelo, LD (December 2009). "Reversible severe combined immunodeficiency phenotype secondary to a mutation of the proton-coupled folate transporter". Clinical immunology (Orlando, Fla.). 133 (3): 287–94. PMID 19740703.
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  25. ^ Zhao, R; Goldman, ID (2013). "Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors". Molecular aspects of medicine. 34 (2–3): 373–85. PMID 23506878.
  26. ^ Desmoulin, SK; Hou, Z; Gangjee, A; Matherly, LH (December 2012). "The human proton-coupled folate transporter: Biology and therapeutic applications to cancer". Cancer biology & therapy. 13 (14): 1355–73. PMID 22954694.
  27. ^ Stark, M; Gonen, N; Assaraf, YG (9 October 2009). "Functional elements in the minimal promoter of the human proton-coupled folate transporter". Biochemical and biophysical research communications. 388 (1): 79–85. PMID 19643086.
  28. ^ Diop-Bove, NK; Wu, J; Zhao, R; Locker, J; Goldman, ID (August 2009). "Hypermethylation of the human proton-coupled folate transporter (SLC46A1) minimal transcriptional regulatory region in an antifolate-resistant HeLa cell line". Molecular cancer therapeutics. 8 (8): 2424–31. PMID 19671745.
  29. ^ Eloranta, JJ; Zaïr, ZM; Hiller, C; Häusler, S; Stieger, B; Kullak-Ublick, GA (November 2009). "Vitamin D3 and its nuclear receptor increase the expression and activity of the human proton-coupled folate transporter". Molecular pharmacology. 76 (5): 1062–71. PMID 19666701.
  30. ^ Gonen, N; Assaraf, YG (29 October 2010). "The obligatory intestinal folate transporter PCFT (SLC46A1) is regulated by nuclear respiratory factor 1". The Journal of biological chemistry. 285 (44): 33602–13. PMID 20724482.
  31. ^ Umapathy, NS; Gnana-Prakasam, JP; Martin, PM; Mysona, B; Dun, Y; Smith, SB; Ganapathy, V; Prasad, PD (November 2007). "Cloning and functional characterization of the proton-coupled electrogenic folate transporter and analysis of its expression in retinal cell types". Investigative ophthalmology & visual science. 48 (11): 5299–305. PMID 17962486.
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External links

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