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Homocysteinemia due to MTHFR deficiency

MedGen UID:
383829
Concept ID:
C1856058
Disease or Syndrome
Synonyms: 5,10-alpha-methylenetetrahydro-folate reductase deficiency; Homocysteinemia due to methylenetetrahydro-folate reductase deficiency; Homocysteinuria due to methylenetetrahydro-folate reductase deficiency; HOMOCYSTINURIA DUE TO DEFICIENCY OF N(5,10)-METHYLENETETRAHYDROFOLATE REDUCTASE ACTIVITY; Methylenetetrahydro-folate reductase deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
 
Gene (location): MTHFR (1p36.22)
OMIM®: 236250
Orphanet: ORPHA395

Definition

Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (Rosenblatt et al., 1992). [from OMIM]

Clinical features

Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
A stroke is a medical emergency. Strokes happen when blood flow to your brain stops. Within minutes, brain cells begin to die. There are two kinds of stroke. The more common kind, called ischemic stroke, is caused by a blood clot that blocks or plugs a blood vessel in the brain. The other kind, called hemorrhagic stroke, is caused by a blood vessel that breaks and bleeds into the brain. Mini-strokes or transient ischemic attacks (TIAs), occur when the blood supply to the brain is briefly interrupted. Symptoms of stroke are . -Sudden numbness or weakness of the face, arm or leg (especially on one side of the body). -Sudden confusion, trouble speaking or understanding speech. -Sudden trouble seeing in one or both eyes. -Sudden trouble walking, dizziness, loss of balance or coordination. -Sudden severe headache with no known cause. If you have any of these symptoms, you must get to a hospital quickly to begin treatment. Acute stroke therapies try to stop a stroke while it is happening by quickly dissolving the blood clot or by stopping the bleeding. Post-stroke rehabilitation helps individuals overcome disabilities that result from stroke damage. Drug therapy with blood thinners is the most common treatment for stroke. . NIH: National Institute of Neurological Disorders and Stroke.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Microcephaly
MedGen UID:
473122
Concept ID:
C0424688
Finding
Occipito-frontal (head) circumference (OFC) less than -3 standard deviations compared to appropriate, age matched, normal standards (Ross JJ, Frias JL 1977, PMID:9683597). Alternatively, decreased size of the cranium.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHomocysteinemia due to MTHFR deficiency
Follow this link to review classifications for Homocysteinemia due to MTHFR deficiency in Orphanet.

Recent clinical studies

Etiology

Shiran A, Remer E, Asmer I, Karkabi B, Zittan E, Cassel A, Barak M, Rozenberg O, Karkabi K, Flugelman MY
Isr Med Assoc J 2015 May;17(5):288-92. PMID: 26137654
Uehara SK, Rosa G
Nutr Res 2008 Nov;28(11):760-6. doi: 10.1016/j.nutres.2008.09.006. PMID: 19083485
Saffroy R, Benyamina A, Pham P, Marill C, Karila L, Reffas M, Debuire B, Reynaud M, Lemoine A
Drug Alcohol Depend 2008 Jul 1;96(1-2):30-6. Epub 2008 Mar 7 doi: 10.1016/j.drugalcdep.2008.01.016. PMID: 18328637
Zittan E, Preis M, Asmir I, Cassel A, Lindenfeld N, Alroy S, Halon DA, Lewis BS, Shiran A, Schliamser JE, Flugelman MY
Am J Physiol Heart Circ Physiol 2007 Jul;293(1):H860-5. Epub 2007 Apr 20 doi: 10.1152/ajpheart.01189.2006. PMID: 17449548
Rozen R
Semin Thromb Hemost 2000;26(3):255-61. doi: 10.1055/s-2000-8470. PMID: 11011843

Diagnosis

Shiran A, Remer E, Asmer I, Karkabi B, Zittan E, Cassel A, Barak M, Rozenberg O, Karkabi K, Flugelman MY
Isr Med Assoc J 2015 May;17(5):288-92. PMID: 26137654
Sahai I, Mochida GH, Grabowski EF, Caruso PA
N Engl J Med 2014 Aug 28;371(9):847-58. doi: 10.1056/NEJMcpc1400833. PMID: 25162892
Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M
Orphanet J Rare Dis 2014 Apr 28;9:65. doi: 10.1186/1750-1172-9-65. PMID: 24775716Free PMC Article
Gessoni G, Valverde S, Canistro R, Trabuio E, Antico F, Manoni F
Minerva Med 2007 Apr;98(2):89-93. PMID: 17519850
Regland B, Johansson BV, Gottfries CG
J Neural Transm Gen Sect 1994;98(2):143-52. PMID: 7734111

Therapy

Shiran A, Remer E, Asmer I, Karkabi B, Zittan E, Cassel A, Barak M, Rozenberg O, Karkabi K, Flugelman MY
Isr Med Assoc J 2015 May;17(5):288-92. PMID: 26137654
Mandaviya PR, Stolk L, Heil SG
Mol Genet Metab 2014 Dec;113(4):243-52. Epub 2014 Oct 14 doi: 10.1016/j.ymgme.2014.10.006. PMID: 25456744
Hoţoleanu C, Porojan-Iuga M, Rusu ML, Andercou A
Rom J Intern Med 2007;45(2):159-64. PMID: 18333369
Regland B, Johansson BV, Gottfries CG
J Neural Transm Gen Sect 1994;98(2):143-52. PMID: 7734111
Rees MM, Rodgers GM
Thromb Res 1993 Sep 1;71(5):337-59. PMID: 8236162

Prognosis

Zittan E, Preis M, Asmir I, Cassel A, Lindenfeld N, Alroy S, Halon DA, Lewis BS, Shiran A, Schliamser JE, Flugelman MY
Am J Physiol Heart Circ Physiol 2007 Jul;293(1):H860-5. Epub 2007 Apr 20 doi: 10.1152/ajpheart.01189.2006. PMID: 17449548
Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R
Nat Genet 1994 Jun;7(2):195-200. doi: 10.1038/ng0694-195. PMID: 7920641
Rees MM, Rodgers GM
Thromb Res 1993 Sep 1;71(5):337-59. PMID: 8236162

Clinical prediction guides

Shiran A, Remer E, Asmer I, Karkabi B, Zittan E, Cassel A, Barak M, Rozenberg O, Karkabi K, Flugelman MY
Isr Med Assoc J 2015 May;17(5):288-92. PMID: 26137654
Pogribny IP, Kutanzi K, Melnyk S, de Conti A, Tryndyak V, Montgomery B, Pogribna M, Muskhelishvili L, Latendresse JR, James SJ, Beland FA, Rusyn I
FASEB J 2013 Jun;27(6):2233-43. Epub 2013 Feb 25 doi: 10.1096/fj.12-227116. PMID: 23439872
Uehara SK, Rosa G
Nutr Res 2008 Nov;28(11):760-6. doi: 10.1016/j.nutres.2008.09.006. PMID: 19083485
Saffroy R, Benyamina A, Pham P, Marill C, Karila L, Reffas M, Debuire B, Reynaud M, Lemoine A
Drug Alcohol Depend 2008 Jul 1;96(1-2):30-6. Epub 2008 Mar 7 doi: 10.1016/j.drugalcdep.2008.01.016. PMID: 18328637
Zittan E, Preis M, Asmir I, Cassel A, Lindenfeld N, Alroy S, Halon DA, Lewis BS, Shiran A, Schliamser JE, Flugelman MY
Am J Physiol Heart Circ Physiol 2007 Jul;293(1):H860-5. Epub 2007 Apr 20 doi: 10.1152/ajpheart.01189.2006. PMID: 17449548

Recent systematic reviews

Bonnot O, Klünemann HH, Sedel F, Tordjman S, Cohen D, Walterfang M
Orphanet J Rare Dis 2014 Apr 28;9:65. doi: 10.1186/1750-1172-9-65. PMID: 24775716Free PMC Article

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