Folate Malabsorption, Hereditary (HFM)

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Disease Ontology 12 DOID:0111678 OMIM 56 229050 KEGG 36 H01252 MeSH 43 C562799 NCIt 49 C156424 SNOMED-CT 67 62578003

ICD10 via Orphanet 33 D52.8 UMLS via Orphanet 72 C0342705 Orphanet 58 ORPHA90045 MedGen 41 C0342705 SNOMED-CT via HPO 68 119250001 127034005 128613002 16331000 165517008 16932000 17944005 197927001 224958001 228156007 234532001 235595009 246545002 247578003 25786006 258211005 26284000 267060006 277843001 302215000 302226006 313307000 36440009 386033004 398151007 398152000 398979000 415116008 42658009 432788009 44913001 45534005 53165003 58593005 62315008 698065002 74035001 7847004 79890006 84757009 84828003 85102008 86854008 91138005 91175000 9748009 more UMLS 71 C0342705

NIH Rare Diseases : ⁵² The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 90045 Definition Hereditary 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. Epidemiology The prevalence is unknown. Approximately 30 cases have been reported to date. Clinical description Disease 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. Etiology HFM 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 methods Diagnosis 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 diagnosis The 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 diagnosis Antenatal 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 counseling HFM is inherited autosomal recessively. Genetic counseling is possible. Management and treatment High 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. Prognosis With 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.

MalaCards based summary : Folate Malabsorption, Hereditary, also known as hereditary folate malabsorption, is related to megaloblastic anemia and hemifacial microsomia, and has symptoms including seizures, ataxia and diarrhea. 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 bone marrow, bone and brain, and related phenotypes are global developmental delay and failure to thrive

Disease Ontology : ¹² A vitamin metabolic disorder characterized by impaired intestinal folate absorption and impaired transport of folate into the central nervous system resulting in megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits that has material basis in homozygous or compound heterozygous mutation in SLC46A1 on chromosome 17q11.2.

Genetics Home Reference : ²⁵ 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. Infants with hereditary folate malabsorption are born with normal amounts of folates in their body because they obtain these vitamins from their mother's blood before birth. They generally begin to show signs and symptoms of the disorder within the first few months of life because their ability to absorb folates from food is impaired. Infants with hereditary folate malabsorption experience feeding difficulties, diarrhea, and failure to gain weight and grow at the expected rate (failure to thrive). Affected individuals usually develop a blood disorder called megaloblastic anemia. Megaloblastic anemia occurs when a person has a low number of red blood cells (anemia), and the remaining red blood cells are larger than normal (megaloblastic). The symptoms of this blood disorder may include decreased appetite, lack of energy, headaches, pale skin, and tingling or numbness in the hands and feet. People with hereditary folate malabsorption may also have a deficiency of white blood cells (leukopenia), leading to increased susceptibility to infections. In addition, they may have a reduction in the amount of platelets (thrombocytopenia), which can result in easy bruising and abnormal bleeding. Some infants with hereditary folate malabsorption exhibit neurological problems such as developmental delay and seizures. Over time, untreated individuals may develop intellectual disability and difficulty coordinating movements (ataxia).

OMIM : ⁵⁶ 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)

KEGG : ³⁶ Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by impaired intestinal folate absorption. HFM is characterized by anemia, hypoimmunoglobulinemia, and recurrent infections. When diagnosed early, the signs and symptoms can be obviated by high oral doses of folates. Recently, several mutations were identified in the proton-coupled folate transporter (PCFT/SLC46A1) gene from patients with HFM.

UniProtKB/Swiss-Prot : ⁷³ 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 : ⁷⁴ Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by loss-of-function... more...

GeneReviews: NBK1673

Clinical features from OMIM:

229050

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

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