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Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase

MedGen UID:
462408
Concept ID:
C3151058
Disease or Syndrome
Synonym: Hypermethioninemia with s-adenosylhomocysteine hydrolase deficiency
SNOMED CT: S-adenosylhomocysteine hydrolase deficiency (724040000); Deficiency of S-adenosylhomocysteine hydrolase (724040000)
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): AHCY (20q11.22)
 
Monarch Initiative: MONDO:0013404
OMIM®: 613752
Orphanet: ORPHA88618

Definition

Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency is an autosomal recessive severe neurometabolic disorder affecting the muscles, liver, and nervous system, resulting in death in infancy (summary by Bas et al., 2020). Other causes of hypermethioninemia include hereditary tyrosinemia (276700), cystathionine beta-synthase deficiency (236200), and methionine adenosyltransferase deficiency (250850). [from OMIM]

Additional description

From MedlinePlus Genetics
Hypermethioninemia is an excess of a particular protein building block (amino acid), called methionine, in the blood. This condition can occur when methionine is not broken down (metabolized) properly in the body.

People with hypermethioninemia often do not show any symptoms. Some individuals with hypermethioninemia exhibit intellectual disability and other neurological problems; delays in motor skills such as standing or walking; sluggishness; muscle weakness; liver problems; unusual facial features; and their breath, sweat, or urine may have a smell resembling boiled cabbage.

Hypermethioninemia can occur with other metabolic disorders, such as homocystinuria, tyrosinemia, and galactosemia, which also involve the faulty breakdown of particular molecules. It can also result from liver disease or excessive dietary intake of methionine from consuming large amounts of protein or a methionine-enriched infant formula. The condition is called primary hypermethioninemia when it is not associated with other metabolic disorders or excess methionine in the diet.  https://medlineplus.gov/genetics/condition/hypermethioninemia

Clinical features

From HPO
Cardiomyopathy
MedGen UID:
209232
Concept ID:
C0878544
Disease or Syndrome
A myocardial disorder in which the heart muscle is structurally and functionally abnormal, in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Decreased hepatic echogenicity
MedGen UID:
1379023
Concept ID:
C4477002
Finding
Reduced echogenicity of liver tissue on sonography, manifested as an increased amount of black on the screen of the sonography device.
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.
Motor delay
MedGen UID:
381392
Concept ID:
C1854301
Finding
A type of Developmental delay characterized by a delay in acquiring motor skills.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Poor head control
MedGen UID:
322809
Concept ID:
C1836038
Finding
Difficulty to maintain correct position of the head while standing or sitting. Infant head lag is observed when the head seems to flop around or lags posteriorly behind the trunk. Several articles have maintained that head lag should be absent by age 3 to 4 months.
Increased variability in muscle fiber diameter
MedGen UID:
336019
Concept ID:
C1843700
Finding
An abnormally high degree of muscle fiber size variation. This phenotypic feature can be observed upon muscle biopsy.
Elevated circulating aspartate aminotransferase concentration
MedGen UID:
57497
Concept ID:
C0151904
Finding
The concentration of aspartate aminotransferase (AST) in the blood circulation is above the upper limit of normal.
Elevated circulating alanine aminotransferase concentration
MedGen UID:
57740
Concept ID:
C0151905
Finding
An abnormally high concentration in the circulation of alanine aminotransferase (ALT).
Hypoalbuminemia
MedGen UID:
68694
Concept ID:
C0239981
Finding
Reduction in the concentration of albumin in the blood.
Hypermethioninemia
MedGen UID:
887708
Concept ID:
C4048705
Disease or Syndrome
An increased concentration of methionine in the blood.
Increased circulating creatine kinase MM isoform
MedGen UID:
1707383
Concept ID:
C5139213
Finding
An increased concentration of the MM isoform of creatine kinase in the blood circulation.
Decreased tissue S-adenosylhomocysteine hydrolase activity
MedGen UID:
1053355
Concept ID:
CN377899
Finding
Concentration or activity of S-adenosylhomocysteine hydrolase (EC 3.3.1.1) below the lower limit of normal. FECH enzyme can be measured in multiple tissues including erythrocytes and liver.
Abnormality of the dentition
MedGen UID:
78084
Concept ID:
C0262444
Finding
Any abnormality of the teeth.
Abnormal facial shape
MedGen UID:
98409
Concept ID:
C0424503
Finding
An abnormal morphology (form) of the face or its components.
Esodeviation
MedGen UID:
1641033
Concept ID:
C4551734
Disease or Syndrome
A manifest or latent ocular deviation in which one or both eyes tends to deviate nasally.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase
Follow this link to review classifications for Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase in Orphanet.

Professional guidelines

PubMed

Park I, Bublil EM, Glavin F, Majtan T
Nutrients 2020 Sep 22;12(9) doi: 10.3390/nu12092895. PMID: 32971905Free PMC Article
Zhang Z, Wang Y, Ma D, Cheng W, Sun Y, Jiang T
J Pediatr Endocrinol Metab 2020 Jan 28;33(1):47-52. doi: 10.1515/jpem-2019-0285. PMID: 31851615
Barić I, Staufner C, Augoustides-Savvopoulou P, Chien YH, Dobbelaere D, Grünert SC, Opladen T, Petković Ramadža D, Rakić B, Wedell A, Blom HJ
J Inherit Metab Dis 2017 Jan;40(1):5-20. Epub 2016 Sep 26 doi: 10.1007/s10545-016-9972-7. PMID: 27671891Free PMC Article

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Methionine +/- Elevated Homocysteine, Homocystinuria (Cystathionine beta-synthase deficiency), 2021

American College of Medical Genetics and Genomics, Algorithm, Elevated Methionine +/- Elevated Homocysteine, 2021

Recent clinical studies

Etiology

Dai X, Liu S, Cheng L, Huang T, Guo H, Wang D, Xia M, Ling W, Xiao Y
Circ Res 2022 May 13;130(10):1565-1582. Epub 2022 Apr 12 doi: 10.1161/CIRCRESAHA.121.320251. PMID: 35410483
Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Zhang Z, Wang Y, Ma D, Cheng W, Sun Y, Jiang T
J Pediatr Endocrinol Metab 2020 Jan 28;33(1):47-52. doi: 10.1515/jpem-2019-0285. PMID: 31851615
Chien YH, Abdenur JE, Baronio F, Bannick AA, Corrales F, Couce M, Donner MG, Ficicioglu C, Freehauf C, Frithiof D, Gotway G, Hirabayashi K, Hofstede F, Hoganson G, Hwu WL, James P, Kim S, Korman SH, Lachmann R, Levy H, Lindner M, Lykopoulou L, Mayatepek E, Muntau A, Okano Y, Raymond K, Rubio-Gozalbo E, Scholl-Bürgi S, Schulze A, Singh R, Stabler S, Stuy M, Thomas J, Wagner C, Wilson WG, Wortmann S, Yamamoto S, Pao M, Blom HJ
Orphanet J Rare Dis 2015 Aug 20;10:99. doi: 10.1186/s13023-015-0321-y. PMID: 26289392Free PMC Article
Mudd SH, Levy HL, Tangerman A, Boujet C, Buist N, Davidson-Mundt A, Hudgins L, Oyanagi K, Nagao M, Wilson WG
Am J Hum Genet 1995 Oct;57(4):882-92. PMID: 7573050Free PMC Article

Diagnosis

Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Zhang Z, Wang Y, Ma D, Cheng W, Sun Y, Jiang T
J Pediatr Endocrinol Metab 2020 Jan 28;33(1):47-52. doi: 10.1515/jpem-2019-0285. PMID: 31851615
Keller R, Chrastina P, Pavlíková M, Gouveia S, Ribes A, Kölker S, Blom HJ, Baumgartner MR, Bártl J, Dionisi-Vici C, Gleich F, Morris AA, Kožich V, Huemer M; individual contributors of the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD), Barić I, Ben-Omran T, Blasco-Alonso J, Bueno Delgado MA, Carducci C, Cassanello M, Cerone R, Couce ML, Crushell E, Delgado Pecellin C, Dulin E, Espada M, Ferino G, Fingerhut R, Garcia Jimenez I, Gonzalez Gallego I, González-Irazabal Y, Gramer G, Juan Fita MJ, Karg E, Klein J, Konstantopoulou V, la Marca G, Leão Teles E, Leuzzi V, Lilliu F, Lopez RM, Lund AM, Mayne P, Meavilla S, Moat SJ, Okun JG, Pasquini E, Pedron-Giner CC, Racz GZ, Ruiz Gomez MA, Vilarinho L, Yahyaoui R, Zerjav Tansek M, Zetterström RH, Zeyda M
J Inherit Metab Dis 2019 Jan;42(1):128-139. doi: 10.1002/jimd.12034. PMID: 30740731
Chou JY
Pharmacol Ther 2000 Jan;85(1):1-9. doi: 10.1016/s0163-7258(99)00047-9. PMID: 10674710
Mudd SH, Levy HL, Tangerman A, Boujet C, Buist N, Davidson-Mundt A, Hudgins L, Oyanagi K, Nagao M, Wilson WG
Am J Hum Genet 1995 Oct;57(4):882-92. PMID: 7573050Free PMC Article

Therapy

Imbard A, Toumazi A, Magréault S, Garcia-Segarra N, Schlemmer D, Kaguelidou F, Perronneau I, Haignere J, de Baulny HO, Kuster A, Feillet F, Alberti C, Guilmin-Crépon S, Benoist JF, Schiff M
Orphanet J Rare Dis 2022 Nov 14;17(1):417. doi: 10.1186/s13023-022-02567-4. PMID: 36376887Free PMC Article
Park I, Bublil EM, Glavin F, Majtan T
Nutrients 2020 Sep 22;12(9) doi: 10.3390/nu12092895. PMID: 32971905Free PMC Article
Furujo M, Kinoshita M, Nagao M, Kubo T
Mol Genet Metab 2012 Nov;107(3):253-6. Epub 2012 Aug 11 doi: 10.1016/j.ymgme.2012.08.002. PMID: 22951388
Tangerman A, Wilcken B, Levy HL, Boers GH, Mudd SH
Metabolism 2000 Aug;49(8):1071-7. doi: 10.1053/meta.2000.7709. PMID: 10954028
Imura K, Okada A
Nutrition 1998 Jan;14(1):143-8. doi: 10.1016/s0899-9007(97)00230-x. PMID: 9437700

Prognosis

Becker PH, Demir Z, Mozer Glassberg Y, Sevin C, Habes D, Imbard A, Mussini C, Rozenfeld Bar Lev M, Davit-Spraul A, Benoist JF, Thérond P, Slama A, Jacquemin E, Gonzales E, Gaignard P
Mol Genet Metab 2021 Jan;132(1):38-43. Epub 2020 Nov 28 doi: 10.1016/j.ymgme.2020.11.007. PMID: 33309011
Wang W, Yang J, Xue J, Mu W, Zhang X, Wu W, Xu M, Gong Y, Liu Y, Zhang Y, Xie X, Gu W, Bai J, Cram DS
BMC Med Genet 2019 Jan 6;20(1):3. doi: 10.1186/s12881-018-0731-5. PMID: 30612563Free PMC Article
Chien YH, Abdenur JE, Baronio F, Bannick AA, Corrales F, Couce M, Donner MG, Ficicioglu C, Freehauf C, Frithiof D, Gotway G, Hirabayashi K, Hofstede F, Hoganson G, Hwu WL, James P, Kim S, Korman SH, Lachmann R, Levy H, Lindner M, Lykopoulou L, Mayatepek E, Muntau A, Okano Y, Raymond K, Rubio-Gozalbo E, Scholl-Bürgi S, Schulze A, Singh R, Stabler S, Stuy M, Thomas J, Wagner C, Wilson WG, Wortmann S, Yamamoto S, Pao M, Blom HJ
Orphanet J Rare Dis 2015 Aug 20;10:99. doi: 10.1186/s13023-015-0321-y. PMID: 26289392Free PMC Article
Couce ML, Bóveda MD, García-Jimémez C, Balmaseda E, Vives I, Castiñeiras DE, Fernández-Marmiesse A, Fraga JM, Mudd SH, Corrales FJ
Mol Genet Metab 2013 Nov;110(3):218-21. Epub 2013 Aug 14 doi: 10.1016/j.ymgme.2013.08.003. PMID: 23993429
Mudd SH, Levy HL, Tangerman A, Boujet C, Buist N, Davidson-Mundt A, Hudgins L, Oyanagi K, Nagao M, Wilson WG
Am J Hum Genet 1995 Oct;57(4):882-92. PMID: 7573050Free PMC Article

Clinical prediction guides

Chien YH, Abdenur JE, Baronio F, Bannick AA, Corrales F, Couce M, Donner MG, Ficicioglu C, Freehauf C, Frithiof D, Gotway G, Hirabayashi K, Hofstede F, Hoganson G, Hwu WL, James P, Kim S, Korman SH, Lachmann R, Levy H, Lindner M, Lykopoulou L, Mayatepek E, Muntau A, Okano Y, Raymond K, Rubio-Gozalbo E, Scholl-Bürgi S, Schulze A, Singh R, Stabler S, Stuy M, Thomas J, Wagner C, Wilson WG, Wortmann S, Yamamoto S, Pao M, Blom HJ
Orphanet J Rare Dis 2015 Aug 20;10:99. doi: 10.1186/s13023-015-0321-y. PMID: 26289392Free PMC Article
Nagao M, Tanaka T, Furujo M
Mol Genet Metab 2013 Dec;110(4):460-4. Epub 2013 Oct 31 doi: 10.1016/j.ymgme.2013.10.013. PMID: 24231718
Avila MA, Berasain C, Torres L, Martín-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballería J, Rodés J, Mato JM
J Hepatol 2000 Dec;33(6):907-14. doi: 10.1016/s0168-8278(00)80122-1. PMID: 11131452
Tangerman A, Wilcken B, Levy HL, Boers GH, Mudd SH
Metabolism 2000 Aug;49(8):1071-7. doi: 10.1053/meta.2000.7709. PMID: 10954028
Mudd SH, Levy HL, Tangerman A, Boujet C, Buist N, Davidson-Mundt A, Hudgins L, Oyanagi K, Nagao M, Wilson WG
Am J Hum Genet 1995 Oct;57(4):882-92. PMID: 7573050Free PMC Article

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2021
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated Methionine +/- Elevated Homocysteine, Homocystinuria (Cystathionine beta-synthase deficiency), 2021
    • ACMG Algorithm, 2021
      American College of Medical Genetics and Genomics, Algorithm, Elevated Methionine +/- Elevated Homocysteine, 2021

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