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Homocystinuria without methylmalonic aciduria

MedGen UID:
929148
•Concept ID:
C4303479
•
Disease or Syndrome
Synonyms: Functional methionine synthase deficiency; functional methionine synthase deficiency; homocystinuria without methylmalonic aciduria; Methylcobalamin deficiency; methylcobalamin deficiency
SNOMED CT: Homocystinuria without methylmalonic aciduria (721225009); Functional methionine synthase deficiency (721225009)
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).
Autosomal recessive inheritance (Orphanet)
 
Monarch Initiative: MONDO:0018964
Orphanet: ORPHA622

Definition

An inborn error of vitamin B12 (cobalamin) metabolism characterised by megaloblastic anaemia, encephalopathy and sometimes, developmental delay, and associated with homocystinuria and hyperhomocysteinemia. There are three types of homocystinuria without methylmalonic aciduria; cblE, cblG and cblD-variant 1 (cblDv1). These disorders are caused by a functional deficiency of the cytoplasmic enzyme methionine synthase (MS), which catalyses remethylation of homocysteine to form methionine. [from SNOMEDCT_US]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • Homocystinuria without methylmalonic aciduria

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
Methylmalonic aciduria: newborn screening in mainland China?
Tu WJ, Chen H, He J
J Pediatr Endocrinol Metab 2013;26(3-4):399-400. doi: 10.1515/jpem-2012-0276. PMID: 23446948

Recent clinical studies

Etiology

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.
Teive HAG, Camargo CHF, Pereira ER, Coutinho L, Munhoz RP
Neurogenetics 2022 Jul;23(3):167-177. Epub 2022 Apr 9 doi: 10.1007/s10048-022-00688-3. PMID: 35397036
Intracellular processing of vitamin B(12) by MMACHC (CblC).
Hannibal L, Jacobsen DW
Vitam Horm 2022;119:275-298. Epub 2022 Mar 15 doi: 10.1016/bs.vh.2022.02.001. PMID: 35337623
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 acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes.
Carrillo-Carrasco N, Venditti CP
J Inherit Metab Dis 2012 Jan;35(1):103-14. Epub 2011 Jul 12 doi: 10.1007/s10545-011-9365-x. PMID: 21748408Free PMC Article
Creatine metabolism in combined methylmalonic aciduria and homocystinuria.
Bodamer OA, Sahoo T, Beaudet AL, O'Brien WE, Bottiglieri T, Stöckler-Ipsiroglu S, Wagner C, Scaglia F
Ann Neurol 2005 Apr;57(4):557-60. doi: 10.1002/ana.20419. PMID: 15786446

Diagnosis

Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review.
Arhip L, Brox-Torrecilla N, Romero I, Motilla M, Serrano-Moreno C, Miguélez M, Cuerda C
Orphanet J Rare Dis 2024 Jan 20;19(1):20. doi: 10.1186/s13023-024-03021-3. PMID: 38245797Free PMC Article
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
Ocular findings in a patient with methylmalonic acidemia and homocystinuria.
Sánchez-Vicente JL, Espiñeira-Periñán MA, López-Herrero F, Balboa-Huguet B, Franco-Ruedas C
J Fr Ophtalmol 2021 Feb;44(2):268-269. Epub 2020 Nov 13 doi: 10.1016/j.jfo.2020.04.035. PMID: 33199039
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
Gene discovery in methylmalonic aciduria and homocystinuria.
Thiele J, Van Raamsdonk JM
Clin Genet 2006 May;69(5):402-3. doi: 10.1111/j.1399-0004.2006.00595c.x. PMID: 16650077

Therapy

Neurodevelopmental and neuropsychiatric disorders in cobalamin C disease: a case report and review of the literature.
Nguyen MG, Tronick L, Modirian F, Mardach R, Besterman AD
Cold Spring Harb Mol Case Stud 2022 Feb;8(2) Epub 2022 Mar 24 doi: 10.1101/mcs.a006179. PMID: 35105663Free 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
Management of hemolytic uremic syndrome.
Loirat C, Saland J, Bitzan M
Presse Med 2012 Mar;41(3 Pt 2):e115-35. Epub 2012 Jan 27 doi: 10.1016/j.lpm.2011.11.013. PMID: 22284541
Adult-onset combined methylmalonic aciduria and homocystinuria (cblC).
Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL
Neurology 2001 Apr 24;56(8):1113. doi: 10.1212/wnl.56.8.1113. PMID: 11320193
Methylmalonic aciduria with homocystinuria.
Ribes A, Vilaseca MA, Briones P, Maya A, Sabater J, Pascual P, Alvarez L, Ros J, Gonzalez Pascual E
J Inherit Metab Dis 1984;7 Suppl 2:129-30. doi: 10.1007/978-94-009-5612-4_39. PMID: 6434865

Prognosis

Late-onset cblC defect: clinical, biochemical and molecular analysis.
Ding S, Ling S, Liang L, Qiu W, Zhang H, Chen T, Zhan X, Xu F, Gu X, Han L
Orphanet J Rare Dis 2023 Sep 28;18(1):306. doi: 10.1186/s13023-023-02890-4. PMID: 37770946Free PMC Article
Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria.
Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, Garbade SF, Hoffmann GF, Okun JG, Mütze U
Nutrients 2023 Jul 28;15(15) doi: 10.3390/nu15153355. PMID: 37571294Free 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
Milder clinical and biochemical phenotypes associated with the c.482G>A (p.Arg161Gln) pathogenic variant in cobalamin C disease: Implications for management and screening.
Almannai M, Marom R, Divin K, Scaglia F, Sutton VR, Craigen WJ, Lee B, Burrage LC, Graham BH
Mol Genet Metab 2017 Sep;122(1-2):60-66. Epub 2017 Jun 29 doi: 10.1016/j.ymgme.2017.06.011. PMID: 28693988Free PMC Article
Management of hemolytic uremic syndrome.
Loirat C, Saland J, Bitzan M
Presse Med 2012 Mar;41(3 Pt 2):e115-35. Epub 2012 Jan 27 doi: 10.1016/j.lpm.2011.11.013. PMID: 22284541

Clinical prediction guides

Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias.
Reischl-Hajiabadi AT, Schnabel E, Gleich F, Mengler K, Lindner M, Burgard P, Posset R, Lommer-Steinhoff S, Grünert SC, Thimm E, Freisinger P, Hennermann JB, Krämer J, Gramer G, Lenz D, Christ S, Hörster F, Hoffmann GF, Garbade SF, Kölker S, Mütze U
J Inherit Metab Dis 2024 Jul;47(4):674-689. Epub 2024 Apr 2 doi: 10.1002/jimd.12731. PMID: 38563533
Late-onset cblC defect: clinical, biochemical and molecular analysis.
Ding S, Ling S, Liang L, Qiu W, Zhang H, Chen T, Zhan X, Xu F, Gu X, Han L
Orphanet J Rare Dis 2023 Sep 28;18(1):306. doi: 10.1186/s13023-023-02890-4. PMID: 37770946Free 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
Creatine metabolism in combined methylmalonic aciduria and homocystinuria.
Bodamer OA, Sahoo T, Beaudet AL, O'Brien WE, Bottiglieri T, Stöckler-Ipsiroglu S, Wagner C, Scaglia F
Ann Neurol 2005 Apr;57(4):557-60. doi: 10.1002/ana.20419. PMID: 15786446
Congenital methylmalonic aciduria--homocystinuria with megaloblastic anemia: observations on response to hydroxocobalamin and on the effect of homocysteine and methionine on the deoxyuridine suppression test.
Carmel R, Bedros AA, Mace JW, Goodman SI
Blood 1980 Apr;55(4):570-9. PMID: 7357085

Recent systematic reviews

Late-onset methylmalonic acidemia and homocysteinemia (cblC disease): systematic review.
Arhip L, Brox-Torrecilla N, Romero I, Motilla M, Serrano-Moreno C, Miguélez M, Cuerda C
Orphanet J Rare Dis 2024 Jan 20;19(1):20. doi: 10.1186/s13023-024-03021-3. PMID: 38245797Free PMC Article

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