U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Homocystinuria due to methylene tetrahydrofolate reductase 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; Homocysteinemia due to MTHFR 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
Source: 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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): MTHFR (1p36.22)
 
Monarch Initiative: MONDO:0009353
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]

Additional description

From MedlinePlus Genetics
The signs and symptoms of homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.\n\nLess common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and 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).\n\nHomocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.  https://medlineplus.gov/genetics/condition/homocystinuria

Clinical features

From HPO
Homocystinuria
MedGen UID:
42485
Concept ID:
C0019880
Disease or Syndrome
Homocystinuria is an inherited disorder in which the body is unable to process certain building blocks of proteins (amino acids) properly. There are multiple forms of homocystinuria, which are distinguished by their signs and symptoms and genetic cause. The most common form of homocystinuria is characterized by nearsightedness (myopia), dislocation of the lens at the front of the eye, an increased risk of abnormal blood clotting, and brittle bones that are prone to fracture (osteoporosis) or other skeletal abnormalities. Some affected individuals also have developmental delay and learning problems.\n\nLess common forms of homocystinuria can cause intellectual disability, failure to grow and gain weight at the expected rate (failure to thrive), seizures, problems with movement, and 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).\n\nThe signs and symptoms of homocystinuria typically develop within the first year of life, although some mildly affected people may not develop features until later in childhood or adulthood.
Paresthesia
MedGen UID:
14619
Concept ID:
C0030554
Disease or Syndrome
Abnormal sensations such as tingling, pricking, or numbness of the skin with no apparent physical cause.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterised by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Stroke
MedGen UID:
52522
Concept ID:
C0038454
Disease or Syndrome
Sudden impairment of blood flow to a part of the brain due to occlusion or rupture of an artery to the brain.
Behavioral abnormality
MedGen UID:
535345
Concept ID:
C0233514
Mental or Behavioral Dysfunction
An abnormality of mental functioning including various affective, behavioural, cognitive and perceptual abnormalities.
Incoordination
MedGen UID:
141714
Concept ID:
C0520966
Finding
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
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.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk. In general, this can refer to neurological diseases but also fractures or other sources of pain that is triggered upon walking. However, in the current context gait disturbance refers to difficulty walking on the basis of a neurological or muscular disease.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Microcephaly
MedGen UID:
1644158
Concept ID:
C4551563
Finding
Head circumference below 2 standard deviations below the mean for age and gender.
Hyperhomocystinemia
MedGen UID:
812677
Concept ID:
C3806347
Finding
An increased concentration of homocystine in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHomocystinuria due to methylene tetrahydrofolate reductase deficiency
Follow this link to review classifications for Homocystinuria due to methylene tetrahydrofolate reductase deficiency in Orphanet.

Recent clinical studies

Etiology

Hale N, Minzola D
AANA J 2020 Aug;88(4):303-306. PMID: 32718428
Jaisson S, Desmons A, Braconnier A, Wynckel A, Rieu P, Gillery P, Garnotel R
Clin Biochem 2020 Jun;80:52-55. Epub 2020 Mar 19 doi: 10.1016/j.clinbiochem.2020.03.010. PMID: 32199937
Ehsani M, Imani A, Moravveji A
Mol Biol Rep 2018 Aug;45(4):621-624. Epub 2018 May 31 doi: 10.1007/s11033-018-4201-0. PMID: 29855758
Cascella M, Arcamone M, Morelli E, Viscardi D, Russo V, De Franciscis S, Belli A, Accardo R, Caliendo D, De Luca E, Di Caprio B, Di Sauro F, Giannoni G, Iermano C, Maciariello M, Marracino M, Cuomo A
J Med Case Rep 2015 Aug 20;9:175. doi: 10.1186/s13256-015-0662-0. PMID: 26289647Free PMC Article
Lossos A, Teltsh O, Milman T, Meiner V, Rozen R, Leclerc D, Schwahn BC, Karp N, Rosenblatt DS, Watkins D, Shaag A, Korman SH, Heyman SN, Gal A, Newman JP, Steiner-Birmanns B, Abramsky O, Kohn Y
JAMA Neurol 2014 Jul 1;71(7):901-4. doi: 10.1001/jamaneurol.2014.116. PMID: 24797679

Diagnosis

Moirangthem A, Saxena D, Masih S, Shambhavi A, Nilay M, Phadke SR
Clin Dysmorphol 2022 Apr 1;31(2):59-65. doi: 10.1097/MCD.0000000000000407. PMID: 34845156
Kaur R, Correa ARE, Thakur S, Kabra M, Gupta N
Indian J Pediatr 2020 Nov;87(11):951-953. Epub 2020 May 26 doi: 10.1007/s12098-020-03290-3. PMID: 32451826
Froese DS, Huemer M, Suormala T, Burda P, Coelho D, Guéant JL, Landolt MA, Kožich V, Fowler B, Baumgartner MR
Hum Mutat 2016 May;37(5):427-38. Epub 2016 Mar 18 doi: 10.1002/humu.22970. PMID: 26872964
Gao L, Kolanuvada B, Naik G, Zhang Y, Zhao M, Sun L, Alaie D, Petrillo RL
Blood Coagul Fibrinolysis 2016 Sep;27(6):720-3. doi: 10.1097/MBC.0000000000000458. PMID: 26650456
Cascella M, Arcamone M, Morelli E, Viscardi D, Russo V, De Franciscis S, Belli A, Accardo R, Caliendo D, De Luca E, Di Caprio B, Di Sauro F, Giannoni G, Iermano C, Maciariello M, Marracino M, Cuomo A
J Med Case Rep 2015 Aug 20;9:175. doi: 10.1186/s13256-015-0662-0. PMID: 26289647Free PMC Article

Therapy

Moirangthem A, Saxena D, Masih S, Shambhavi A, Nilay M, Phadke SR
Clin Dysmorphol 2022 Apr 1;31(2):59-65. doi: 10.1097/MCD.0000000000000407. PMID: 34845156
Hale N, Minzola D
AANA J 2020 Aug;88(4):303-306. PMID: 32718428
Jaisson S, Desmons A, Braconnier A, Wynckel A, Rieu P, Gillery P, Garnotel R
Clin Biochem 2020 Jun;80:52-55. Epub 2020 Mar 19 doi: 10.1016/j.clinbiochem.2020.03.010. PMID: 32199937
Vieira D, Florindo C, Tavares de Almeida I, Macário MC
BMJ Case Rep 2020 Mar 10;13(3) doi: 10.1136/bcr-2019-232241. PMID: 32161077Free PMC Article
Gao L, Kolanuvada B, Naik G, Zhang Y, Zhao M, Sun L, Alaie D, Petrillo RL
Blood Coagul Fibrinolysis 2016 Sep;27(6):720-3. doi: 10.1097/MBC.0000000000000458. PMID: 26650456

Prognosis

Yverneau M, Leroux S, Imbard A, Gleich F, Arion A, Moreau C, Nassogne MC, Szymanowski M, Tardieu M, Touati G, Bueno M, Chapman KA, Chien YH, Huemer M, Ješina P, Janssen MCH, Kölker S, Kožich V, Lavigne C, Lund AM, Mochel F, Morris A, Pons MR, Porras-Hurtado GL, Benoist JF, Damaj L, Schiff M; E-HOD Consortium.
J Inherit Metab Dis 2022 Jul;45(4):848-861. Epub 2022 May 9 doi: 10.1002/jimd.12504. PMID: 35460084
Huemer M, Mulder-Bleile R, Burda P, Froese DS, Suormala T, Zeev BB, Chinnery PF, Dionisi-Vici C, Dobbelaere D, Gökcay G, Demirkol M, Häberle J, Lossos A, Mengel E, Morris AA, Niezen-Koning KE, Plecko B, Parini R, Rokicki D, Schiff M, Schimmel M, Sewell AC, Sperl W, Spiekerkoetter U, Steinmann B, Taddeucci G, Trejo-Gabriel-Galán JM, Trefz F, Tsuji M, Vilaseca MA, von Kleist-Retzow JC, Walker V, Zeman J, Baumgartner MR, Fowler B
J Inherit Metab Dis 2016 Jan;39(1):115-24. Epub 2015 May 30 doi: 10.1007/s10545-015-9860-6. PMID: 26025547Free PMC Article
Diekman EF, de Koning TJ, Verhoeven-Duif NM, Rovers MM, van Hasselt PM
JAMA Neurol 2014 Feb;71(2):188-94. doi: 10.1001/jamaneurol.2013.4915. PMID: 24323041
Urreizti R, Moya-García AA, Pino-Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez-Dueñas B, Pineda M, González V, Artuch R, Baldellou A, Vilarinho L, Fowler B, Ribes A, Sánchez-Jiménez F, Grinberg D, Balcells S
Clin Genet 2010 Nov;78(5):441-8. doi: 10.1111/j.1399-0004.2010.01391.x. PMID: 20236116
Tallur KK, Johnson DA, Kirk JM, Sandercock PA, Minns RA
Dev Med Child Neurol 2005 Jan;47(1):53-6. doi: 10.1017/s0012162205000095. PMID: 15686290

Clinical prediction guides

Yverneau M, Leroux S, Imbard A, Gleich F, Arion A, Moreau C, Nassogne MC, Szymanowski M, Tardieu M, Touati G, Bueno M, Chapman KA, Chien YH, Huemer M, Ješina P, Janssen MCH, Kölker S, Kožich V, Lavigne C, Lund AM, Mochel F, Morris A, Pons MR, Porras-Hurtado GL, Benoist JF, Damaj L, Schiff M; E-HOD Consortium.
J Inherit Metab Dis 2022 Jul;45(4):848-861. Epub 2022 May 9 doi: 10.1002/jimd.12504. PMID: 35460084
Moirangthem A, Saxena D, Masih S, Shambhavi A, Nilay M, Phadke SR
Clin Dysmorphol 2022 Apr 1;31(2):59-65. doi: 10.1097/MCD.0000000000000407. PMID: 34845156
Burda P, Suormala T, Heuberger D, Schäfer A, Fowler B, Froese DS, Baumgartner MR
J Inherit Metab Dis 2017 Mar;40(2):297-306. Epub 2016 Oct 14 doi: 10.1007/s10545-016-9987-0. PMID: 27743313
Lossos A, Teltsh O, Milman T, Meiner V, Rozen R, Leclerc D, Schwahn BC, Karp N, Rosenblatt DS, Watkins D, Shaag A, Korman SH, Heyman SN, Gal A, Newman JP, Steiner-Birmanns B, Abramsky O, Kohn Y
JAMA Neurol 2014 Jul 1;71(7):901-4. doi: 10.1001/jamaneurol.2014.116. PMID: 24797679
Urreizti R, Moya-García AA, Pino-Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez-Dueñas B, Pineda M, González V, Artuch R, Baldellou A, Vilarinho L, Fowler B, Ribes A, Sánchez-Jiménez F, Grinberg D, Balcells S
Clin Genet 2010 Nov;78(5):441-8. doi: 10.1111/j.1399-0004.2010.01391.x. PMID: 20236116

Recent systematic reviews

Zeng H, He D, Zhao Y, Liu NG, Xie H
Arch Gynecol Obstet 2021 Apr;303(4):1089-1098. Epub 2020 Oct 31 doi: 10.1007/s00404-020-05851-5. PMID: 33128585
Chen F, Wen T, Lv Q, Liu F
Nutr Cancer 2020;72(7):1211-1218. Epub 2019 Oct 29 doi: 10.1080/01635581.2019.1677924. PMID: 31661627
Huemer M, Kožich V, Rinaldo P, Baumgartner MR, Merinero B, Pasquini E, Ribes A, Blom HJ
J Inherit Metab Dis 2015 Nov;38(6):1007-19. Epub 2015 Mar 12 doi: 10.1007/s10545-015-9830-z. PMID: 25762406Free PMC Article
Support Center