MCID: FLT009
MIFTS: 36

Folate Malabsorption, Hereditary

Categories: Genetic diseases, Rare diseases, Gastrointestinal diseases, Metabolic diseases, Blood diseases

Aliases & Classifications for Folate Malabsorption, Hereditary

MalaCards integrated aliases for Folate Malabsorption, Hereditary:

Name: Folate Malabsorption, Hereditary 53 49 13 69
Hereditary Folate Malabsorption 23 49 24 55 71 36
Congenital Folate Malabsorption 23 49 24 55
Congenital Defect of Folate Absorption 49 24 28
Folic Acid Transport Defect 49 24
Hfm 71

Characteristics:

Orphanet epidemiological data:

55
hereditary folate malabsorption
Inheritance: Autosomal recessive; Prevalence: <1/1000000 (Worldwide); Age of onset: Infancy,Neonatal;

OMIM:

53
Inheritance:
autosomal recessive

Miscellaneous:
onset in infancy
early diagnosis and proper treatment with folate replacement therapy can avoid neurologic sequelae


HPO:

31
folate malabsorption, hereditary:
Onset and clinical course infantile onset
Inheritance autosomal recessive inheritance


Classifications:



Summaries for Folate Malabsorption, Hereditary

NIH Rare Diseases : 49 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.Orpha Number: 90045Disease definitionHereditary folate malabsorption (HFM) is an inherited disorder of folate transport characterized by a systemic and central nervous system (CNS) folate deficiency manifesting as megaloblastic anemia, failure to thrive, diarrhea and/or oral mucositis, immunologic dysfunction and neurological disorders.EpidemiologyThe prevalence is unknown. Approximately 30 cases have been reported to date.Clinical descriptionDisease onset usually occurs a few months after birth. Manifestations include failure to thrive, diarrhea and/or mouth ulcers, various neurological manifestations (motor impairment, seizures, developmental delay, cognitive and behavioral disorders), megaloblastic anemia and hypoimmunoglobulinemia. Megaloblastic anemia is the primary manifestation of HFM and can be very severe if untreated. Hypoimmunoglobulinemia results in unusual infections with Pneumocystis jiroveccii, C. difficile and cytomegalovirus (CMV) which can be recurrent and life-threatening in undiagnosed infants. Neurological manifestations may be the presenting symptoms in some but are absent in others. Seizures, if present, begin in infancy or later in childhood. Intracranial calcifications have been observed in some.EtiologyHFM is caused by mutations in the SLC46A1 gene found on chromosome 17q11.2 which encodes the proton-coupled folate transporter (PCFT). PCFT is essential for intestinal folate absorption and transport of folates across the blood-cerebrospinal fluid (CSF) barrier. A defect in this protein leads to a systemic folate and CNS folate deficiency. Infants cannot absorb adequate folate from breast milk/formula and become deficient once their stores accumulated during gestation are exhausted.Diagnostic methodsDiagnosis is based on clinical and laboratory findings. It is confirmed by findings of an impaired absorption of an oral folate load (even after correction of serum folate concentration) and a low CSF folate concentration (0-1.5nM). Bone marrow biopsy confirms the presence of megaloblastic anemia. Sequence analysis of the SLC46A1 coding region can identify any mutations present in the gene, also confirming diagnosis of HFM.Differential diagnosisThe immunodeficiency seen in HFM may resemble severe combined immune deficiency (SCID; see this term). Other differential diagnoses include methionine synthase deficiency with megaloblastic anemia and developmental delay, formiminoglutamic aciduria, tyrosinemia type 1, methylenetetrahydrofolate reductase deficiency and erythroleukemia (see these terms).Antenatal diagnosisAntenatal diagnosis is possible via prenatal testing. Screening of newborns with a family history of HFM allows for early diagnosis and treatment with folate immediately after birth, before symptoms occur.Genetic counselingHFM is inherited autosomal recessively. Genetic counseling is possible.Management and treatmentHigh dose oral or parenteral 5-formyltetrahydrofolate (5-formylTHF) and oral L-5-methyltetrahydrofolate (L-5-methylTHF) are the two types of reduced folates used to treat HFM. Dosage is monitored and adjusted (individualized for each patient) so that the CSF folate levels remain within the normal range (around 100nM in infants-2 year olds). Folic acid should not be used as it binds to folate receptors and blocks folate transport. If anemia is severe, a transfusion may be necessary. Early treatment with reduced folates before the appearance of symptoms can prevent the metabolic consequences of HFM. Patients should have regular blood tests to monitor complete blood count, serum and CSF folate and homocysteine concentrations and serum immunoglobulin concentrations.PrognosisWith proper treatment the prognosis is good and reversal of most of the systemic consequences of the disease is usually achieved. Only when untreated is the prognosis poor.Visit the Orphanet disease page for more resources. Last updated: 10/1/2012

MalaCards based summary : Folate Malabsorption, Hereditary, also known as hereditary folate malabsorption, is related to hemifacial microsomia and epilepsy occipital calcifications, and has symptoms including seizures, diarrhea and nausea and vomiting. An important gene associated with Folate Malabsorption, Hereditary is SLC46A1 (Solute Carrier Family 46 Member 1), and among its related pathways/superpathways are Vitamin digestion and absorption and Mineral absorption. Affiliated tissues include brain, bone and testes.

Genetics Home Reference : 24 Hereditary folate malabsorption is a disorder that interferes with the body's ability to absorb certain B vitamins (called folates) from food. Folates are important for many cell functions, including the production of DNA and its chemical cousin, RNA.

OMIM : 53 Hereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system (summary by Qiu et al., 2006). (229050)

UniProtKB/Swiss-Prot : 71 Hereditary folate malabsorption: Rare autosomal recessive disorder characterized by impaired intestinal folate absorption with folate deficiency resulting in anemia, hypoimmunoglobulinemia with recurrent infections, and recurrent or chronic diarrhea. In many patients, neurological abnormalities such as seizures or mental retardation become apparent during early childhood, attributed to impaired transport of folates into the central nervous system. When diagnosed early, the disorder can be treated by administration of folate. If untreated, it can be fatal and, if treatment is delayed, the neurological defects can become permanent.

Wikipedia : 72 Hereditary folate malabsorption (HFM - OMIM #229050) is a rare autosomal recessive disorder caused by... more...

GeneReviews: NBK1673

Related Diseases for Folate Malabsorption, Hereditary

Diseases related to Folate Malabsorption, Hereditary via text searches within MalaCards or GeneCards Suite gene sharing:

# Related Disease Score Top Affiliating Genes
1 hemifacial microsomia 11.7
2 epilepsy occipital calcifications 11.1
3 craniofacial microsomia 10.9
4 combined immunodeficiency, x-linked 9.9
5 pancytopenia 9.9
6 cerebritis 9.9
7 cerebral folate deficiency 9.9

Graphical network of the top 20 diseases related to Folate Malabsorption, Hereditary:



Diseases related to Folate Malabsorption, Hereditary

Symptoms & Phenotypes for Folate Malabsorption, Hereditary

Symptoms via clinical synopsis from OMIM:

53
NeurologicCentralNervousSystem:
ataxia
seizures
athetosis
hypotonia
head lag
more
GrowthOther:
failure to thrive

NeurologicPeripheralNervousSystem:
peripheral neuropathy

Immunology:
recurrent infections
increased susceptibility to pneumocystis and cytomegalovirus infections
hypoimmunoglobulinemia

LaboratoryAbnormalities:
decreased serum folate
decreased csf folate
low plasma methionine
increased urinary formiminoglutamic acid (figlu)

AbdomenGastrointestinal:
diarrhea
poor feeding
folate malabsorption

NeurologicBehavioralPsychiatricManifestations:
irritability

Hematology:
thrombocytopenia
neutropenia
leukopenia
megaloblastic anemia, folate-responsive

HeadAndNeckMouth:
oral ulcers


Clinical features from OMIM:

229050

Human phenotypes related to Folate Malabsorption, Hereditary:

55 31 (show all 39)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 seizures 55 31 frequent (33%) Frequent (79-30%) HP:0001250
2 diarrhea 55 31 hallmark (90%) Very frequent (99-80%) HP:0002014
3 nausea and vomiting 55 31 hallmark (90%) Very frequent (99-80%) HP:0002017
4 hyperreflexia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001347
5 failure to thrive 55 31 hallmark (90%) Very frequent (99-80%) HP:0001508
6 cerebral calcification 55 31 occasional (7.5%) Occasional (29-5%) HP:0002514
7 behavioral abnormality 55 31 frequent (33%) Frequent (79-30%) HP:0000708
8 global developmental delay 55 31 hallmark (90%) Very frequent (99-80%) HP:0001263
9 recurrent respiratory infections 55 31 occasional (7.5%) Occasional (29-5%) HP:0002205
10 gastroesophageal reflux 55 31 frequent (33%) Frequent (79-30%) HP:0002020
11 immunodeficiency 55 31 occasional (7.5%) Occasional (29-5%) HP:0002721
12 abnormality of movement 55 31 hallmark (90%) Very frequent (99-80%) HP:0100022
13 skeletal muscle atrophy 55 31 occasional (7.5%) Occasional (29-5%) HP:0003202
14 pancytopenia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001876
15 pallor 55 31 hallmark (90%) Very frequent (99-80%) HP:0000980
16 peripheral neuropathy 55 31 frequent (33%) Frequent (79-30%) HP:0009830
17 thrombocytopenia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001873
18 decreased antibody level in blood 55 31 hallmark (90%) Very frequent (99-80%) HP:0004313
19 anorexia 55 31 hallmark (90%) Very frequent (99-80%) HP:0002039
20 cheilitis 55 31 hallmark (90%) Very frequent (99-80%) HP:0100825
21 recurrent urinary tract infections 55 31 occasional (7.5%) Occasional (29-5%) HP:0000010
22 eosinophilia 55 31 occasional (7.5%) Occasional (29-5%) HP:0001880
23 glossitis 55 31 hallmark (90%) Very frequent (99-80%) HP:0000206
24 megaloblastic anemia 55 31 hallmark (90%) Very frequent (99-80%) HP:0001889
25 ataxia 31 HP:0001251
26 athetosis 31 HP:0002305
27 intellectual disability 31 HP:0001249
28 malabsorption 31 HP:0002024
29 dyskinesia 31 HP:0100660
30 feeding difficulties in infancy 31 HP:0008872
31 irritability 31 HP:0000737
32 abnormality of the immune system 55 Very frequent (99-80%)
33 recurrent infections 31 HP:0002719
34 neutropenia 31 HP:0001875
35 leukopenia 31 HP:0001882
36 oral ulcer 31 HP:0000155
37 generalized hypotonia 31 HP:0001290
38 basal ganglia calcification 31 HP:0002135
39 folate-responsive megaloblastic anemia 31 HP:0004851

UMLS symptoms related to Folate Malabsorption, Hereditary:


seizures, diarrhea, athetosis, ataxia

Drugs & Therapeutics for Folate Malabsorption, Hereditary

Search Clinical Trials , NIH Clinical Center for Folate Malabsorption, Hereditary

Genetic Tests for Folate Malabsorption, Hereditary

Genetic tests related to Folate Malabsorption, Hereditary:

# Genetic test Affiliating Genes
1 Congenital Defect of Folate Absorption 28 SLC46A1

Anatomical Context for Folate Malabsorption, Hereditary

MalaCards organs/tissues related to Folate Malabsorption, Hereditary:

38
Brain, Bone, Testes, Bone Marrow, Skeletal Muscle

Publications for Folate Malabsorption, Hereditary

Articles related to Folate Malabsorption, Hereditary:

(show all 22)
# Title Authors Year
1
The proton-coupled folate transporter (PCFT-SLC46A1) and the syndrome of systemic and cerebral folate deficiency of infancy: Hereditary folate malabsorption. ( 27664775 )
2016
2
Reversible pancytopenia and immunodeficiency in a patient with hereditary folate malabsorption. ( 25504888 )
2015
3
Hereditary folate malabsorption with extensive intracranial calcification. ( 25638192 )
2015
4
Impact of folate therapy on combined immunodeficiency secondary to hereditary folate malabsorption. ( 24691418 )
2014
5
The first Chinese case report of hereditary folate malabsorption with a novel mutation on SLC46A1. ( 24534056 )
2014
6
A novel deletion mutation in the proton-coupled folate transporter (PCFT; SLC46A1) in a Nicaraguan child with hereditary folate malabsorption. ( 23816405 )
2013
7
Functional roles of the A335 and G338 residues of the proton-coupled folate transporter (PCFT-SLC46A1) mutated in hereditary folate malabsorption. ( 22843796 )
2012
8
A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding. ( 22345511 )
2012
9
A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency. ( 21346251 )
2011
10
Identification of novel mutations in the proton-coupled folate transporter (PCFT-SLC46A1) associated with hereditary folate malabsorption. ( 21333572 )
2011
11
Prevalence of a loss-of-function mutation in the proton-coupled folate transporter gene (PCFT-SLC46A1) causing hereditary folate malabsorption in Puerto Rico. ( 21489556 )
2011
12
Functional roles of aspartate residues of the proton-coupled folate transporter (PCFT-SLC46A1); a D156Y mutation causing hereditary folate malabsorption. ( 20805364 )
2010
13
Mutation of the proton-coupled folate transporter gene (PCFT-SLC46A1) in Turkish siblings with hereditary folate malabsorption. ( 20795774 )
2010
14
A novel PCFT gene mutation (p.Cys66LeufsX99) causing hereditary folate malabsorption. ( 20005757 )
2010
15
Properties of the Arg376 residue of the proton-coupled folate transporter (PCFT-SLC46A1) and a glutamine mutant causing hereditary folate malabsorption. ( 20686069 )
2010
16
Hereditary folate malabsorption: a positively charged amino acid at position 113 of the proton-coupled folate transporter (PCFT/SLC46A1) is required for folic acid binding. ( 19508863 )
2009
17
The clinical course and genetic defect in the PCFT gene in a 27-year-old woman with hereditary folate malabsorption. ( 18718264 )
2008
18
A novel loss-of-function mutation in the proton-coupled folate transporter from a patient with hereditary folate malabsorption reveals that Arg 113 is crucial for function. ( 18559978 )
2008
19
The spectrum of mutations in the PCFT gene, coding for an intestinal folate transporter, that are the basis for hereditary folate malabsorption. ( 17446347 )
2007
20
Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. ( 17129779 )
2006
21
Hereditary folate malabsorption: family report and review of the literature. ( 11807405 )
2002
22
Hereditary Folate Malabsorption ( 20301716 )
1993

Variations for Folate Malabsorption, Hereditary

UniProtKB/Swiss-Prot genetic disease variations for Folate Malabsorption, Hereditary:

71
# Symbol AA change Variation ID SNP ID
1 SLC46A1 p.Arg113Ser VAR_032825 rs80338770
2 SLC46A1 p.Gly147Arg VAR_032826 rs80338771
3 SLC46A1 p.Ser318Arg VAR_032827 rs80338772
4 SLC46A1 p.Arg376Trp VAR_032828 rs80338773
5 SLC46A1 p.Pro425Arg VAR_032829 rs80338774
6 SLC46A1 p.Arg113Cys VAR_058210 rs80338770
7 SLC46A1 p.Asp156Tyr VAR_067960 rs281875210
8 SLC46A1 p.Ala335Asp VAR_067961 rs281875208
9 SLC46A1 p.Gly338Arg VAR_067962 rs281875209
10 SLC46A1 p.Arg376Gln VAR_067963 rs281875211

ClinVar genetic disease variations for Folate Malabsorption, Hereditary:

6 (show all 17)
# Gene Variation Type Significance SNP ID Assembly Location
1 SLC46A1 NM_080669.5(SLC46A1): c.1274C> G (p.Pro425Arg) single nucleotide variant Pathogenic rs80338774 GRCh37 Chromosome 17, 26727674: 26727674
2 SLC46A1 NM_080669.5(SLC46A1): c.197_198delGCinsAA (p.Cys66Ter) indel Pathogenic rs154623632 GRCh37 Chromosome 17, 26732935: 26732936
3 SLC46A1 NM_080669.5(SLC46A1): c.439G> C (p.Gly147Arg) single nucleotide variant Pathogenic rs80338771 GRCh37 Chromosome 17, 26732276: 26732276
4 SLC46A1 SLC46A1, 1-BP INS, 17C insertion Pathogenic
5 SLC46A1 NM_080669.5(SLC46A1): c.1004C> A (p.Ala335Asp) single nucleotide variant Pathogenic rs281875208 GRCh37 Chromosome 17, 26731711: 26731711
6 SLC46A1 NM_080669.5(SLC46A1): c.204_205delCC (p.Asn68Lysfs) deletion Pathogenic rs397515391 GRCh37 Chromosome 17, 26732928: 26732929
7 SLC46A1 NM_080669.5(SLC46A1): c.1012G> C (p.Gly338Arg) single nucleotide variant Pathogenic rs281875209 GRCh37 Chromosome 17, 26731703: 26731703
8 SLC46A1 NM_080669.5(SLC46A1): c.1127G> A (p.Arg376Gln) single nucleotide variant Pathogenic rs281875211 GRCh37 Chromosome 17, 26729294: 26729294
9 SLC46A1 NM_080669.5(SLC46A1): c.194dupG (p.Cys66Leufs) duplication Pathogenic rs397515573 GRCh37 Chromosome 17, 26732939: 26732939
10 SLC46A1 NM_080669.5(SLC46A1): c.23_24insC (p.Glu9Glyfs) insertion Pathogenic rs397515574 GRCh37 Chromosome 17, 26733110: 26733110
11 SLC46A1 NM_080669.5(SLC46A1): c.466G> T (p.Asp156Tyr) single nucleotide variant Pathogenic rs281875210 GRCh37 Chromosome 17, 26732249: 26732249
12 SLC46A1 NM_080669.5(SLC46A1): c.1082-1G> A single nucleotide variant Pathogenic rs80338775 GRCh37 Chromosome 17, 26729340: 26729340
13 SLC46A1 NM_080669.5(SLC46A1): c.194delG (p.Gly65Alafs) deletion Pathogenic rs80338769 GRCh37 Chromosome 17, 26732939: 26732939
14 SLC46A1 NM_080669.5(SLC46A1): c.337C> A (p.Arg113Ser) single nucleotide variant Pathogenic rs80338770 GRCh37 Chromosome 17, 26732378: 26732378
15 SLC46A1 NM_080669.5(SLC46A1): c.954C> G (p.Ser318Arg) single nucleotide variant Pathogenic rs80338772 GRCh37 Chromosome 17, 26731761: 26731761
16 SLC46A1 NM_080669.5(SLC46A1): c.1126C> T (p.Arg376Trp) single nucleotide variant Pathogenic rs80338773 GRCh37 Chromosome 17, 26729295: 26729295
17 SLC46A1 NM_080669.5(SLC46A1): c.337C> T (p.Arg113Cys) single nucleotide variant Pathogenic rs80338770 GRCh37 Chromosome 17, 26732378: 26732378

Expression for Folate Malabsorption, Hereditary

Search GEO for disease gene expression data for Folate Malabsorption, Hereditary.

Pathways for Folate Malabsorption, Hereditary

Pathways related to Folate Malabsorption, Hereditary according to KEGG:

36
# Name Kegg Source Accession
1 Vitamin digestion and absorption hsa04977
2 Mineral absorption hsa04978

GO Terms for Folate Malabsorption, Hereditary

Sources for Folate Malabsorption, Hereditary

3 CDC
7 CNVD
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11 DGIdb
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41 MeSH
42 MESH via Orphanet
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65 SNOMED-CT via HPO
66 SNOMED-CT via Orphanet
67 TGDB
68 Tocris
69 UMLS
70 UMLS via Orphanet
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