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Methylmalonic aciduria and homocystinuria

MedGen UID:
978076
•Concept ID:
CN293516
•
Disease or Syndrome
Synonyms: Methylmalonic acidemia and homocystinemia; Methylmalonic acidemia with homocystinuria
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).
X-linked recessive inheritance
MedGen UID:
375779
•Concept ID:
C1845977
•
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
See: This record
Autosomal recessive inheritance (Orphanet)
X-linked recessive inheritance (Orphanet)
 
Related genes: LMBRD1, MMADHC, MMACHC, ABCD4, PRDX1
 
Monarch Initiative: MONDO:0016826
OMIM® Phenotypic series: PS277400
Orphanet: ORPHA26

Definition

A rare inborn error of vitamin B12 (cobalamin) metabolism characterized by megaloblastic anemia, lethargy, failure to thrive, developmental delay, intellectual deficit and seizures. There are four complementation classes of cobalamin defects (cblC, cblD, cblF and cblJ) that are responsible for methylmalonic acidemia - homocystinuria (methylmalonic acidemia - homocystinuria cblC, cblD cblF and cblJ). [from ORDO]

Professional guidelines

PubMed

The genotype analysis and prenatal genetic diagnosis among 244 pedigrees with methylmalonic aciduria in China.
Hu S, Kong X
Taiwan J Obstet Gynecol 2022 Mar;61(2):290-298. doi: 10.1016/j.tjog.2022.02.017. PMID: 35361390
Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.
Hu S, Mei S, Liu N, Kong X
BMC Med Genet 2018 Aug 29;19(1):154. doi: 10.1186/s12881-018-0666-x. PMID: 30157807Free PMC Article
Prenatal diagnosis using genetic sequencing and identification of a novel mutation in MMACHC.
Zong Y, Liu N, Zhao Z, Kong X
BMC Med Genet 2015 Jul 7;16:48. doi: 10.1186/s12881-015-0196-8. PMID: 26149271Free PMC Article

Recent clinical studies

Etiology

The Value of 1H-MRS and MRI in Combined Methylmalonic Aciduria and Homocystinuria.
Cheng A, Yao R, Cao W, Yu H
J Comput Assist Tomogr 2019 Jul/Aug;43(4):559-562. doi: 10.1097/RCT.0000000000000854. PMID: 30839328Free PMC Article
Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity.
Beck BB, van Spronsen F, Diepstra A, Berger RM, Kömhoff M
Pediatr Nephrol 2017 May;32(5):733-741. Epub 2016 Jun 11 doi: 10.1007/s00467-016-3399-0. PMID: 27289364Free PMC Article
Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.
Gizicki R, Robert MC, Gómez-López L, Orquin J, Decarie JC, Mitchell GA, Roy MS, Ospina LH
Ophthalmology 2014 Jan;121(1):381-386. Epub 2013 Oct 11 doi: 10.1016/j.ophtha.2013.08.034. PMID: 24126030
Early-onset combined methylmalonic aciduria and homocystinuria: neuroradiologic findings.
Rossi A, Cerone R, Biancheri R, Gatti R, Schiaffino MC, Fonda C, Zammarchi E, Tortori-Donati P
AJNR Am J Neuroradiol 2001 Mar;22(3):554-63. PMID: 11237984Free PMC Article
Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).
Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR
J Inherit Metab Dis 1997 Aug;20(4):528-38. doi: 10.1023/a:1005353530303. PMID: 9266389

Diagnosis

The genotype analysis and prenatal genetic diagnosis among 244 pedigrees with methylmalonic aciduria in China.
Hu S, Kong X
Taiwan J Obstet Gynecol 2022 Mar;61(2):290-298. doi: 10.1016/j.tjog.2022.02.017. PMID: 35361390
Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists.
Kalantari S, Brezzi B, Bracciamà V, Barreca A, Nozza P, Vaisitti T, Amoroso A, Deaglio S, Manganaro M, Porta F, Spada M
Orphanet J Rare Dis 2022 Feb 2;17(1):33. doi: 10.1186/s13023-022-02179-y. PMID: 35109910Free PMC Article
Combined Methylmalonic Aciduria and Homocystinuria Presenting as Pulmonary Hypertension.
Gupta A, Kabra M, Gupta N
Indian J Pediatr 2021 Dec;88(12):1244-1246. Epub 2021 Sep 12 doi: 10.1007/s12098-021-03938-8. PMID: 34510336
Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria.
Hu S, Mei S, Liu N, Kong X
BMC Med Genet 2018 Aug 29;19(1):154. doi: 10.1186/s12881-018-0666-x. PMID: 30157807Free PMC Article
Oral and craniofacial findings in a patient with methylmalonic aciduria and homocystinuria: review and a case report.
D'Alessandro G, Tagariello T, Piana G
Minerva Stomatol 2010 Mar;59(3):129-37. PMID: 20357739

Therapy

The MMACHC variant c.158T>C: Mild clinical and biochemical phenotypes and marked hydroxocobalamin response in cblC patients.
Demaret T, Bédard K, Soucy JF, Watkins D, Allard P, Levtova A, O'Brien A, Brunel-Guitton C, Rosenblatt DS, Mitchell GA
Mol Genet Metab 2024 May;142(1):108345. Epub 2024 Feb 10 doi: 10.1016/j.ymgme.2024.108345. PMID: 38387306
Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists.
Kalantari S, Brezzi B, Bracciamà V, Barreca A, Nozza P, Vaisitti T, Amoroso A, Deaglio S, Manganaro M, Porta F, Spada M
Orphanet J Rare Dis 2022 Feb 2;17(1):33. doi: 10.1186/s13023-022-02179-y. PMID: 35109910Free PMC Article
Hyperhomocysteinemia: a trigger for complement-mediated TMA?
Bernards J, Doubel P, Meeus G, Lerut E, Corveleyn A, Van Den Heuvel LP, Meersseman W, Kuypers DK, Claes KJ
Acta Clin Belg 2021 Feb;76(1):65-69. Epub 2019 Aug 11 doi: 10.1080/17843286.2019.1649039. PMID: 31401947
Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity.
Beck BB, van Spronsen F, Diepstra A, Berger RM, Kömhoff M
Pediatr Nephrol 2017 May;32(5):733-741. Epub 2016 Jun 11 doi: 10.1007/s00467-016-3399-0. PMID: 27289364Free PMC Article
Cobalamin C mutation (methylmalonic aciduria and homocystinuria) in adolescence. A treatable cause of dementia and myelopathy.
Shinnar S, Singer HS
N Engl J Med 1984 Aug 16;311(7):451-4. doi: 10.1056/NEJM198408163110707. PMID: 6749192

Prognosis

Hyperhomocysteinemia: a trigger for complement-mediated TMA?
Bernards J, Doubel P, Meeus G, Lerut E, Corveleyn A, Van Den Heuvel LP, Meersseman W, Kuypers DK, Claes KJ
Acta Clin Belg 2021 Feb;76(1):65-69. Epub 2019 Aug 11 doi: 10.1080/17843286.2019.1649039. PMID: 31401947
First Chinese case of successful pregnancy with combined methylmalonic aciduria and homocystinuria, cblC type.
Liu Y, Wang Q, Li X, Ding Y, Song J, Yang Y
Brain Dev 2015 Mar;37(3):286-91. Epub 2014 Jun 25 doi: 10.1016/j.braindev.2014.06.007. PMID: 24974159
Long-term visual outcome of methylmalonic aciduria and homocystinuria, cobalamin C type.
Gizicki R, Robert MC, Gómez-López L, Orquin J, Decarie JC, Mitchell GA, Roy MS, Ospina LH
Ophthalmology 2014 Jan;121(1):381-386. Epub 2013 Oct 11 doi: 10.1016/j.ophtha.2013.08.034. PMID: 24126030
Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC).
Rosenblatt DS, Aspler AL, Shevell MI, Pletcher BA, Fenton WA, Seashore MR
J Inherit Metab Dis 1997 Aug;20(4):528-38. doi: 10.1023/a:1005353530303. PMID: 9266389
A cobalamin metabolic defect with homocystinuria, methylmalonic aciduria and macrocytic anemia.
Mamlok RJ, Isenberg JN, Rassin DK, Norcross K, Tallan HH
Neuropediatrics 1986 May;17(2):94-9. doi: 10.1055/s-2008-1052508. PMID: 2873525

Clinical prediction guides

The lysosomal protein ABCD4 can transport vitamin B(12) across liposomal membranes in vitro.
Kitai K, Kawaguchi K, Tomohiro T, Morita M, So T, Imanaka T
J Biol Chem 2021 Jan-Jun;296:100654. Epub 2021 May 3 doi: 10.1016/j.jbc.2021.100654. PMID: 33845046Free PMC Article
Hyperhomocysteinemia: a trigger for complement-mediated TMA?
Bernards J, Doubel P, Meeus G, Lerut E, Corveleyn A, Van Den Heuvel LP, Meersseman W, Kuypers DK, Claes KJ
Acta Clin Belg 2021 Feb;76(1):65-69. Epub 2019 Aug 11 doi: 10.1080/17843286.2019.1649039. PMID: 31401947
The Value of 1H-MRS and MRI in Combined Methylmalonic Aciduria and Homocystinuria.
Cheng A, Yao R, Cao W, Yu H
J Comput Assist Tomogr 2019 Jul/Aug;43(4):559-562. doi: 10.1097/RCT.0000000000000854. PMID: 30839328Free PMC Article
Renal thrombotic microangiopathy in patients with cblC defect: review of an under-recognized entity.
Beck BB, van Spronsen F, Diepstra A, Berger RM, Kömhoff M
Pediatr Nephrol 2017 May;32(5):733-741. Epub 2016 Jun 11 doi: 10.1007/s00467-016-3399-0. PMID: 27289364Free PMC Article
Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations.
Morel CF, Lerner-Ellis JP, Rosenblatt DS
Mol Genet Metab 2006 Aug;88(4):315-21. Epub 2006 May 22 doi: 10.1016/j.ymgme.2006.04.001. PMID: 16714133

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