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Congenital defect of folate absorption

MedGen UID:
83348
Concept ID:
C0342705
Disease or Syndrome
Synonyms: Congenital folate malabsorption; Folic acid transport defect; Hereditary Folate Malabsorption
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Autosomal recessive inheritance refers to genetic conditions that occur only when mutations are present in both copies of a given gene (i.e., the person is homozygous for a mutation, or carries two different mutations of the same gene, a state referred to as compound heterozygosity).
SNOMED CT: Congenital defect of folate absorption (62578003); Congenital malabsorption of folic acid (62578003); Folic acid transport defect (62578003); Hereditary folate malabsorption (62578003); Folate transport defect (62578003); Congenital folate malabsorption (27798002)
 
Gene: SLC46A1
Cytogenetic location: 17q11.2
OMIM: 229050

Disease characteristics

Excerpted from the GeneReview: Hereditary Folate Malabsorption
Hereditary folate malabsorption (HFM) is characterized by folate deficiency with impaired intestinal folate absorption and impaired folate transport into the central nervous system (CNS). Findings include poor feeding and failure to thrive, anemia often accompanied by leukopenia and/or thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections with unusual organisms. Neurologic manifestations include developmental delays, cognitive and motor impairment, behavioral disorders and, frequently, seizures. [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  Diagnosis  |  Clinical Description  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  References  |  Chapter Notes
Authors:
Ndeye Diop-Bove  |  David Kronn  |  I David Goldman   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/229050
From GHR
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).  http://ghr.nlm.nih.gov/condition/hereditary-folate-malabsorption

Clinical features

Recurrent urinary tract infections
MedGen UID:
500878
Concept ID:
CN000011
Finding
Repeated infections of the urinary tract.
Oral ulcer
MedGen UID:
504369
Concept ID:
CN000151
Finding
Erosion of the mucous mebrane of the mouth with local excavation of the surface, resulting from the sloughing of inflammatory necrotic tissue.
Glossitis
MedGen UID:
504392
Concept ID:
CN000199
Finding
Inflammation of the tongue.
Irritability
MedGen UID:
5898
Concept ID:
C0022107
Finding
Abnormal or excessive excitability with easily triggered anger, annoyance, or impatience.
Behavioral abnormality
MedGen UID:
425007
Concept ID:
CN000665
Finding
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Ataxia
MedGen UID:
504767
Concept ID:
CN001146
Finding
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Global developmental delay
MedGen UID:
504774
Concept ID:
CN001157
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Basal ganglia calcification
MedGen UID:
505119
Concept ID:
CN001935
Finding
The presence of `calcium deposition` (MPATH:36) affecting one or more structures of the `basal ganglia` (FMA:84013).
Athetosis
MedGen UID:
505190
Concept ID:
CN002093
Finding
Athetosis (from the Greek word for 'changeable' or 'unfixed') refers to an inability to sustain the muscles of the fingers, toes, tongue, or any other group of muscles in a fixed position. Instead, posture is interrupted by slow, purposeless involuntary movements.
Peripheral neuropathy
MedGen UID:
506330
Concept ID:
CN008687
Finding
Peripheral neuropathy is a general term for any disorder of the `peripheral nervous system` (FMA:9903). The main clinical features used to classify peripheral neuropathy are distribution, type (mainly demyelinating versus mainly axonal), duration, and course.
Dyskinesia
MedGen UID:
506509
Concept ID:
CN117552
Finding
A movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements.
Basal ganglia calcification
MedGen UID:
505119
Concept ID:
CN001935
Finding
The presence of `calcium deposition` (MPATH:36) affecting one or more structures of the `basal ganglia` (FMA:84013).
Pallor
MedGen UID:
504674
Concept ID:
CN000918
Finding
Abnormally `pale` (PATO:0000328) `skin` (FMA:7163).
Neutropenia
MedGen UID:
18030
Concept ID:
C0027947
Disease or Syndrome
An abnormal decrease in the number of neutrophils, a type of white blood cell.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Abnormality of eosinophils
MedGen UID:
428282
Concept ID:
CN001699
Finding
An `eosinophil` (CL:0000771) abnormality.
Leukopenia
MedGen UID:
504985
Concept ID:
CN001702
Finding
An abnormal decreased number of `leukocytes` (CL:0000738) in the `blood` (FMA:9670).
Megaloblastic anemia
MedGen UID:
504989
Concept ID:
CN001708
Finding
Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).
Bone marrow hypocellularity
MedGen UID:
505824
Concept ID:
CN004897
Finding
A reduced number of hematopoietic cells present in the bone marrow.
Neutropenia
MedGen UID:
18030
Concept ID:
C0027947
Disease or Syndrome
An abnormal decrease in the number of neutrophils, a type of white blood cell.
Recurrent urinary tract infections
MedGen UID:
500878
Concept ID:
CN000011
Finding
Repeated infections of the urinary tract.
Abnormality of eosinophils
MedGen UID:
428282
Concept ID:
CN001699
Finding
An `eosinophil` (CL:0000771) abnormality.
Leukopenia
MedGen UID:
504985
Concept ID:
CN001702
Finding
An abnormal decreased number of `leukocytes` (CL:0000738) in the `blood` (FMA:9670).
Muscular hypotonia
MedGen UID:
504768
Concept ID:
CN001147
Finding
Muscular hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle), often involving reduced muscle strength. Hypotonia is characterized by a diminished resistance to passive stretching.

Recent clinical studies

Etiology

Obeid R, Holzgreve W, Pietrzik K
J Perinat Med 2013 Sep 1;41(5):469-83. doi: 10.1515/jpm-2012-0256. PMID: 23482308
Maki KC, Ndife LI, Kelley KM, Lawless AL, Brooks JR, Wright SB, Shields JM, Dicklin MR
J Acad Nutr Diet 2012 Jul;112(7):1062-7. Epub 2012 May 11 doi: 10.1016/j.jand.2012.03.001. [Epub ahead of print] PMID: 22579722
Stern SJ, Matok I, Kapur B, Koren G
J Obstet Gynaecol Can 2012 Apr;34(4):374-8. PMID: 22472339
Houghton LA, Gray AR, Rose MC, Miller JC, Hurthouse NA, Gregory JF 3rd
Am J Clin Nutr 2011 Jul;94(1):136-41. Epub 2011 May 18 doi: 10.3945/ajcn.110.004549. [Epub ahead of print] PMID: 21593499Free PMC Article
Stern SJ, Matok I, Kapur B, Koren G
Ther Drug Monit 2011 Jun;33(3):336-40. doi: 10.1097/FTD.0b013e318219407a. PMID: 21572389

Diagnosis

De Grazia S, Carlomagno G, Unfer V, Cavalli P
Expert Opin Drug Deliv 2012 Sep;9(9):1033-9. Epub 2012 Jul 5 doi: 10.1517/17425247.2012.701616. [Epub ahead of print] PMID: 22724555
Whitehead VM
Br J Haematol 2006 Jul;134(2):125-36. doi: 10.1111/j.1365-2141.2006.06133.x. PMID: 16846473
Calvani M Jr, Parisi P, Guaitolini C, Parisi G, Paolone G
Eur J Pediatr 2001 May;160(5):288-92. PMID: 11388596
Frenkel EP, Yardley DA
Hematol Oncol Clin North Am 2000 Oct;14(5):1079-100, viii. PMID: 11005035
Barber RC, Lammer EJ, Shaw GM, Greer KA, Finnell RH
Mol Genet Metab 1999 Jan;66(1):1-9. doi: 10.1006/mgme.1998.2787. PMID: 9973541

Therapy

Obeid R, Holzgreve W, Pietrzik K
J Perinat Med 2013 Sep 1;41(5):469-83. doi: 10.1515/jpm-2012-0256. PMID: 23482308
Maki KC, Ndife LI, Kelley KM, Lawless AL, Brooks JR, Wright SB, Shields JM, Dicklin MR
J Acad Nutr Diet 2012 Jul;112(7):1062-7. Epub 2012 May 11 doi: 10.1016/j.jand.2012.03.001. [Epub ahead of print] PMID: 22579722
Stern SJ, Matok I, Kapur B, Koren G
J Obstet Gynaecol Can 2012 Apr;34(4):374-8. PMID: 22472339
Houghton LA, Gray AR, Rose MC, Miller JC, Hurthouse NA, Gregory JF 3rd
Am J Clin Nutr 2011 Jul;94(1):136-41. Epub 2011 May 18 doi: 10.3945/ajcn.110.004549. [Epub ahead of print] PMID: 21593499Free PMC Article
Stern SJ, Matok I, Kapur B, Koren G
Ther Drug Monit 2011 Jun;33(3):336-40. doi: 10.1097/FTD.0b013e318219407a. PMID: 21572389

Prognosis

Stern SJ, Matok I, Kapur B, Koren G
J Obstet Gynaecol Can 2012 Apr;34(4):374-8. PMID: 22472339
Stern SJ, Matok I, Kapur B, Koren G
Ther Drug Monit 2011 Jun;33(3):336-40. doi: 10.1097/FTD.0b013e318219407a. PMID: 21572389
Matherly LH, Taub JW
Leuk Lymphoma 1996 May;21(5-6):359-68. doi: 10.3109/10428199609093433. PMID: 9172800
Garré ML, Relling MV, Kalwinsky D, Dodge R, Crom WR, Abromowitch M, Pui CH, Evans WE
J Pediatr 1987 Oct;111(4):606-12. PMID: 2958611
Niebyl JR, Blake DA, Rocco LE, Baumgardner R, Mellits ED
Cleft Palate J 1985 Jan;22(1):20-8. PMID: 3868431

Clinical prediction guides

De Grazia S, Carlomagno G, Unfer V, Cavalli P
Expert Opin Drug Deliv 2012 Sep;9(9):1033-9. Epub 2012 Jul 5 doi: 10.1517/17425247.2012.701616. [Epub ahead of print] PMID: 22724555
Stern SJ, Matok I, Kapur B, Koren G
J Obstet Gynaecol Can 2012 Apr;34(4):374-8. PMID: 22472339
Stern SJ, Matok I, Kapur B, Koren G
Ther Drug Monit 2011 Jun;33(3):336-40. doi: 10.1097/FTD.0b013e318219407a. PMID: 21572389
Johansson M, Witthöft CM, Bruce A, Jägerstad M
Eur J Nutr 2002 Dec;41(6):279-86. doi: 10.1007/s00394-002-0388-9. PMID: 12474072
Boddie AM, Dedlow ER, Nackashi JA, Opalko FJ, Kauwell GP, Gregory JF 3rd, Bailey LB
Am J Clin Nutr 2000 Jul;72(1):154-8. PMID: 10871574

Recent systematic reviews

Hovdenak N, Haram K
Eur J Obstet Gynecol Reprod Biol 2012 Oct;164(2):127-32. Epub 2012 Jul 6 doi: 10.1016/j.ejogrb.2012.06.020. [Epub ahead of print] PMID: 22771225
Shankar P, Boylan M, Sriram K
Nutrition 2010 Nov-Dec;26(11-12):1031-7. Epub 2010 Apr 3 doi: 10.1016/j.nut.2009.12.003. [Epub ahead of print] PMID: 20363593
Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, Hopp J, Ting TY, Hauser WA, Thurman D, Kaplan PW, Robinson JN, French JA, Wiebe S, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Shafer PO, Le Guen CL; American Academy of Neurology; American Epilepsy Society
Epilepsia 2009 May;50(5):1247-55. PMID: 19507305
Harden CL, Pennell PB, Koppel BS, Hovinga CA, Gidal B, Meador KJ, Hopp J, Ting TY, Hauser WA, Thurman D, Kaplan PW, Robinson JN, French JA, Wiebe S, Wilner AN, Vazquez B, Holmes L, Krumholz A, Finnell R, Shafer PO, Le Guen C; American Academy of Neurology; American Epilepsy Society
Neurology 2009 Jul 14;73(2):142-9. Epub 2009 Apr 27 doi: 10.1212/WNL.0b013e3181a6b325. [Epub ahead of print] PMID: 19398680Free PMC Article
Fairfield KM, Fletcher RH
JAMA 2002 Jun 19;287(23):3116-26. PMID: 12069675

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